WO2022175689A1

WO2022175689A1 - Treatment

Info

Publication number: WO2022175689A1
Application number: PCT/GB2022/050471
Authority: WO
Inventors: Morten Sommer; Mads JELLINGSØ; Philippe Andres; Rona SMITH; Thomas HIEMSTRA
Original assignee: Cambridge Enterprise Limited
Priority date: 2021-02-22
Filing date: 2022-02-21
Publication date: 2022-08-25
Also published as: GB202102488D0

Abstract

The invention relates to formulations comprising niclosamide, or a pharmaceutically acceptable salt thereof, and a cyclodextrin for use in the treatment or prevention of a respiratory viral infection in a subject wherein the subject is undergoing dialysis, a kidney transplant recipient, or has vasculitis, an auto-immune kidney disease or glomerulonephritis; and wherein the formulation is administered to the subject intranasally.

Description

TREATMENT

[0001] This invention relates to pharmaceutical formulations comprising a niclosamide, or a pharmaceutically acceptable salt thereof, and a cyclodextrin, for use in the intranasal treatment of respiratory viral infections in a subject that is undergoing dialysis, a kidney transplant recipient, or has vasculitis, an auto-immune kidney disease or glomerulonephritis.

BACKGROUND

[0002] Coronaviruses are a group of enveloped and non-segmented positive-sense RNA viruses with very large genome size ranging from approximately 27 to 34 kb. Infections with human strains HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1 usually cause mild, self-limiting respiratory infections, such as the common cold (Fehr et al. Coronaviruses: Methods and Protocols, Maier, H. J.; Bickerton, E.; Britton, P. ,Eds. Springer New York: New York, NY, 2015; pp 1-232015 and Corman et al., Adv. Virus Res., J., Eds. Academic Press: 2018; Vol. 100, pp 163-1882018). However certain highly pathogenic coronaviruses have emerged. SARS-CoV, MERS-CoV and SARS-CoV-2, have caused severe human disease pandemics associated with high morbidity and mortality.

[0003] The clinical manifestations of COVID-19 range from asymptomatic infection to mild, upper respiratory tract infections to severe viral pneumonia with associated respiratory failure and death. Some patients will also go on to develop multi-organ failure, with kidney, cardiac and neurological complications of SARS-CoV-2. The frequency of severe disease in hospitalised patients can be as high as 30%. Many potential treatments are being assessed in randomised treatment trials. The UK RECOVERY trial has demonstrated that dexamethasone reduced deaths by one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021). There was no benefit in patients not requiring ventilatory support. The ACCT-1 trial showed a shorter recovery time 11 days (95%CI, 9 to 12) versus 15 days (95% Cl, 13 to 19) in remdesivir-treated patients. A number of other treatment options have demonstrated no benefit against COVID-19, including hydroxychloroquine and lopinavir-ritonavir.

[0004] In contrast, there are currently no drugs proven to prevent COVID-19 or to reduce the severity of illness if given as prophylaxis. Although vaccines are now available, there remains a need for other prophylactic agents until vaccine use becomes widespread globally and effectiveness and durability is established, particularly in immunocompromised individuals. [0005] The lack of effective treatment for coronavirus infections poses a great challenge to clinical management and highlights the urgent need to fine new treatments for viral infections such as coronavirus infections.

[0006] Wang et al. (Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020, https://doi.org/10.1038/s41422-020- 0282-0) screened antiviral drugs and identified that nitazoxanide, remdesivir and chloroquine, inhibit the SARS-CoV-2 at low-micromolar concentrations in Vero E6 cells with EC50 values of 2.12 pm, 0.77 pm and 1.13 pm, respectively.

[0007] Wu et al. (Inhibition of severe acute respiratory syndrome coronavirus replication by niclosamide, Antimicrob. Agents Chemother. 2004, 48, 2693-2696) found that niclosamide inhibits SARS-CoV replication and totally abolished viral antigen synthesis at a concentration of 1.56 pm. Niclosamide suppressed cytopathic effect (CPE) of SARS-CoV at concentration as low as 1 pm and inhibited SARS-CoV replication with an EC50 value of less than 0.1 pm in Vero E6 cells (Wen et al., J. Med. Chem. 2007, 50, 4087-4095.). Niclosamide was later found be a very potent inhibitor of SARS-CoV2 with an IC50 of 280 nM (Joun et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, The Lancet, https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30183-5/fulltext).

[0008] Xu et al. (ACS Infect. Dis. 2020, published on line 3 March 2020 https://doi.org/10.1021/acsinfecdis.0c00052) discloses that niclosamide is effective against certain viral infections. However, this publication concludes that the, low aqueous solubility, poor absorption and low oral bioavailability would limit its clinical development as an antiviral agent.

[0009] Cabitra et al., JCI Insight. 2019; 4(15):e128414 discloses the treatment of mice using niclosamide dissolved in corn oil and administered by I.P. injection showed that niclosamide reduced mucus production and secretion, as well as bronchoconstriction, and showed additional anti-inflammatory effects in asthmatic mice.

[0010] Niclosamide (trade names are for instance Yomesan®, Tredemine®) is currently approved and marketed for the oral treatment of tapeworm infections with administration of a single 2 g regimen or 2 g daily for 7 days in adults and children (> 2 years of age). The PK analysis revealed that after oral administration, between 2-25% of the administered dose was detected in the urine, which can be considered as the minimum level of absorption. When treating human volunteers each with a single oral dose of 2,000 mg niclosamide, maximal serum concentration of niclosamide was equivalent to 0.25-6. Opg/mL (0.76 - 18.3pM). The wide concentration range was caused by the intraindividual absorption differences. Niclosamide is only partially absorbed from intestinal tract, and the absorbed part is rapidly eliminated by the kidneys. Niclosamide has several other weaknesses such as low absorption and oral bioavailability (F = 10%) which may hamper its extensive clinical development as a systemic agent.

[0011] WO 2017/157997 discloses certain compositions comprising niclosamide for the topical treatment of conditions such as atopic dermatitis. WO 2020/039073 discloses data showing that niclosamide has anti-inflammatory effects when applied topically to the skin of patients with atopic dermatitis. Topical application of niclosamide modulated numerous inflammatory biomarkers.

[0012] Patients with kidney disease requiring dialysis, in receipt of a kidney transplant, or with auto-immune diseases that might affect kidney function and require immunosuppression (e.g. vasculitis, systemic lupus erythematosus (SLE), and glomerular diseases) appear to be vulnerable to COVID-19 and at exceptionally high risk of adverse outcomes.

[0013] Dialysis patients typically need to attend their dialysis centre 3 times per week for at least 4 hours at a time and travel to dialysis centres by ambulance, car or taxi. It is impossible for them to self-isolate. Further, patients receiving dialysis may be less likely to benefit from admission to intensive care due to their comorbidity and the perceived prognostically deleterious impact of end-stage kidney disease. Those dialysis patients contracting COVID-19 have a 26% risk of death from the disease. To date, 11 % of the UK’s in- centre dialysis population has contracted COVID-19.

[0014] Kidney transplant recipients are immunosuppressed and are at increased risk of infections (including viruses)with attendant morbidity (Cowan, J. et al. Incidence Rate of Post-Kidney Transplant Infection: A Retrospective Cohort Study Examining Infection Rates at a Large Canadian Multicenter Tertiary-Care Facility. Can J Kidney Health Dis 5, 2054358118799692 (2018).4. Academy of Medical Sciences. Preparing for a challenging winter 2020/2021. (2020)). Chronic Kidney Disease is itself recognised as a risk factor for severe infections. The combination of immunosuppression and reduced glomerular filtration rate (GFR) render kidney transplant recipients at particular risk of COVID-19 since regular healthcare contact is imperative for most patients.

[0015] Vasculitis patients suffer with serious relapsing remitting auto-immune disease that results in the requirementfor a considerable burden of immunosuppression. The disease itself often results in organ damage, particularly renal and pulmonary damage, and individuals have significant comorbidity. Patients with vasculitis are thought to be at high risk of contracting COVID-19 leading to severe disease, and even death. [0016] Therefore there remains an urgent need to identify effective treatments for respiratory viral infections, particularly COVID-19.

BRIEF SUMMARY OF THE DISCLOSURE

[0017] According to a first aspect of the present invention there is provided a formulation comprising niclosamide, or a pharmaceutically acceptable salt thereof, and a cyclodextrin, for use in the treatment or prevention of a respiratory viral infection in a subject in need thereof; wherein the formulation is administered to the subject intranasally; and the subject is selected from (i) a subject undergoing dialysis, (ii) a kidney transplant recipient and (iii) a subject with vasculitis, systemic lupus erythematosus (SLE), an auto-immune kidney disease or glomerulonephritis.

[0018] Also provided is method for treating or preventing a respiratory viral infection in a subject in need thereof, the method comprising the intranasal administration of a formulation comprising niclosamide, or a pharmaceutically acceptable salt thereof, and a cyclodextrin; and wherein the subject is selected from (i) a subject undergoing dialysis, (ii) a kidney transplant recipient and (iii) a subject with vasculitis, systemic lupus erythematosus (SLE), an auto-immune kidney disease or glomerulonephritis.

[0019] In some embodiments the subject is selected from (i) a subject undergoing dialysis,

(ii) a kidney transplant recipient and (iii) a subject with vasculitis, an auto-immune kidney disease or glomerulonephritis.

[0020] In some embodiments the subject is a subject undergoing dialysis. It may be that the subject undergoing dialysis selected from: centre haemodialysis, home haemodialysis and peritoneal dialysis.

[0021] In some embodiments subject has glomerulonephritis. Glomerulonephritis is a group of disease that cause inflammation and damage to glomerular tissue. The glomerulonephritis may be selected from: minimal change nephropathy, focal segmental glomerulosclerosis (FSGS), IgA nephropathy, primary membranous nephropathy, membranoproliferative glomerulonephritis and lupus nephritis.

[0022] Patients with kidney disease or recipients of a kidney transplant are often treated with immunosuppressant therapies. The compromised or weakened immune system put such patients at high risk of contracting and developing sever forms of COVID-19. Accordingly in certain embodiments the subject is treated concurrently with an immunosuppressant therapy. The term “treated concurrently” includes subjects that were treated with an immunosuppressant therapy prior to administration of the niclosamide formulation, as well as subjects that are treated with an immunosuppressant therapy during treatment with the niclosamide formulation.

[0023] In some embodiments the subject has been or is treated with an immunosuppressant therapy selected from one or more of: a calcineurin inhibitor, a purine synthesis inhibitor, a inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitor, a T cell (lymphocyte) co-stimulation blocker, a folic acid derivative, an IL-6 receptor inhibitor, a T-cell activation inhibitor, a dihydroo rotate dehydrogenase (DHODH) inhibitor, a corticosteroid, an anti-TNF therapy (e.g. an anti-TNF antibody or fusion protein), a B-lymphocyte stimulator (BLyS) inhibitor, an alkylating agent, an anti-CD20 therapy (e.g. an anti-CD20 antibody), and an anti-CD52 therapy (e.g. an anti-CD52 antibody).

[0024] In some embodiments the subject has been or is treated with an immunosuppressant therapy selected from: one or more of ciclosporin, tacrolimus, azathioprine, or mycophenolic acid, or a prodrug thereof (e.g. mycophenolate mofetil), belatacept, methotrexate, tocilizumab, abatacept, leflunomide, prednisolone, sirolimus, an anti-TNF therapy (e.g. infliximab, adalimumab, or etanercept), belimumab, cyclophosphamide, rituximab and alemtuzumab.

[0025] In some embodiments, the niclosamide is present in the free-acid form in the formulation. Alternatively, the formulation may comprise a pharmaceutically acceptable salt of niclosamide, preferably niclosamide ethanolamine.

[0026] The formulation may be in a form suitable for intranasal administration. For example, it may be that the formulation is in the form of a solid (e.g. a powder).

[0027] In some embodiments the formulation is in the form of a suspension, a dispersion or a solution comprising the niclosamide, or a pharmaceutically acceptable salt thereof, and a cyclodextrin in a pharmaceutically acceptable solvent. In other words, the formulation may be a liquid formulation. Solutions and suspensions comprising niclosamide, or a pharmaceutically acceptable salt thereof, and a cyclodextrin, may be any of the solutions or suspensions as described herein.

[0028] The pharmaceutically acceptable solvent may comprise water, i.e. the solution or suspension may be an aqueous solution or an aqueous suspension. In some embodiments the solvent is water. In some embodiments, the solvent comprises a co-solvent. Certain co solvents may be useful to aid solubilisation of the niclosamide, or a pharmaceutically acceptable salt thereof, and/or the cyclodextrin, and/or to help stabilise the solution. In certain embodiments the co-solvent is selected from ethanol, propylene glycol, glycerol, polyethylene glycol (e.g. a polyethylene glycol (PEG) with an average molecular weight of less than 600, such as PEG 200, PEG 300 or PEG 400. In some embodiments the co solvent is selected from propylene glycol and glycerol. In some embodiments the co-solvent is not a PEG. In some embodiments the co-solvent is not ethanol. In certain embodiments the co-solvents is DMSO. A co-solvent may be present in the formulation in an amount of from about 0 % to about 20 %, from about 0.1 % to about 15 %, from about 0.2 % to about 12 % by weight, from about 0.3 % to about 10 %, from about 0.4 % to about 8 %, from about 0.5 % to about 6 %, from about 0.6 % to about 5 %, from about 0.7 % to about 4 %, from about 0.8 % to about 2 %, from about 0.9 % to about 1 % by weight, based on the weight of the solution or suspension.

[0029] In certain embodiments the niclosamide, or a pharmaceutically acceptable salt thereof, is present in the formulation an amount of about 0.01 % to about 10 % by weight of the formulation. For example, the niclosamide, or a pharmaceutically acceptable salt thereof is present in an amount of 0.05 % to 10 %, 0.1 % to 9 %, 0.05 % to 8 %, 0.5 % to 8 %, 1 % to 8 %, 1.5 % to 8 %, 2 % to 8 %, 2.5 % to 8 %, 3 % to 8 %, 3.5 % to 8 %, 4 % to 8 %, 4.5 % to 8 %, 5 % to 8 %, 5.5 % to 8 %, 6 % to 8 %, 3 % to 7 %, 3.5 % to 7.5 %, 3.5 % to 7 %, 3.5 % to 6.5 %, 3.5 % to 6 %, 3.5 % to 5.5 %, 4 % to 7 %, 4 % to 7 %, 4 % to 6.5 %, 4 % to 6 %, 4 % to 5.5 %, 4.5 % to 7 %, 4.5 % to 6.5 %, 4.5 % to 6.5 % or 4.5 % to 5.5 % by weight of the formulation.

[0030] In some embodiments the niclosamide, or a pharmaceutically acceptable salt thereof is present in the formulation in an amount of from about 0.05 to about 5 %, from about 0.5 to about 4%, from about 0.1 to about 3%, from about 0.2 to about 2 %, from about 0.5 to about 1.8%, from about 0.5 to about 1.5%, from about 0.8 to about 1.5%, from about 0.8 to about 1.2%, from about 0.9 to 1.1%, from about 1 to about 3% or from about 1.5 to about 2% by weight of a liquid formulation. Thus it may be that the niclosamide, or a pharmaceutically acceptable salt is present in the liquid formulation in an amount of about 0.1 %, about 0.2%, about 0.3 %, about 0.4 %, about 0.5 %, about 0.6 %, about 0.7 %, about 0.8 %, about 0.9 %, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6% about 1.7%, about 1.8% about 1.9%, about 2 %, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5 %, about 3 %, about 4% or about 5 % by weight of the liquid formulation. In a preferred embodiment the liquid formulation comprises about 1 % by weight of the niclosamide, or a pharmaceutically acceptable salt thereof. The amounts of the niclosamide present in the liquid formulation is applicable to any of the formulations described herein, for example a solution comprising niclosamide or a pharmaceutically acceptable salt thereof; a suspension comprising niclosamide or a pharmaceutically acceptable salt thereof. [0031] In certain embodiments the liquid formulations of the invention provide high concentrations of solubilised niclosamide, or a pharmaceutically acceptable salt thereof. In certain embodiments the niclosamide, or a pharmaceutically acceptable salt thereof, is present in the liquid formulation at a concentration of from about 0.1 to about 100 mg/ml, from about 0.2 to about 90 mg/ml, from about 0.3 to about 80 mg/ml, from about 0.5 to about 75 mg/ml, from about 0.6 to about 70 mg/ml, from about 0.7 to about 65 mg/ml, from about 0.8 to about 60 mg/ml, from about 0.9 to about 60 mg/ml, or from about 1 to about 50 mg/ml. In some embodiments, the niclosamide, or a pharmaceutically acceptable salt thereof, is present in the liquid formulation at a concentration of from about 2 to about 45 mg/ml, from about 3 to about 40 mg/ml, from about 4 to about 40 mg/ml, from about 4 to about 35 mg/ml, from about 5 to about 30 mg/ml, from about 5 to about 25 mg/ml, from about 5 to about 15 mg/ml, from about 7 to about 20 mg/ml, from about 7 to about 15 mg/ml, from about 8 to about 15 mg/ml, from about 9 to about 12 mg/ml, or from about 10 to about 11 mg/ml.

[0032] In some embodiments the niclosamide, or a pharmaceutically acceptable salt thereof is present in the formulation in an amount of about 0.05 to 5 % by weight of a solid formulation. Thus it may be that the niclosamide, or a pharmaceutically acceptable salt thereof is present in the solid formulation in an amount of about 0.05 % to 10 %, 0.05 % to 8 %, 0.5 % to 8 %, 1 % to 8 %, 1.5 % to 8 %, 2 % to 8 %, 2.5 % to 8 %, 3 % to 8 %, 3.5 % to 8 %, 4 % to 8 %, 4.5 % to 8 %, 5 % to 8 %, 5.5 % to 8 %, 6 % to 8 %, 3 % to 7 %, 3.5 % to 7.5 %, 3.5 % to 7 %, 3.5 % to 6.5 %, 3.5 % to 6 %, 3.5 % to 5.5 %, 4 % to 7 %, 4 % to 7 %, 4 % to 6.5 %, 4 % to 6 %, 4 % to 5.5 %, 4.5 % to 7 %, 4.5 % to 6.5 %, 4.5 % to 6.5 %, 4.5 % to 6 % or 5 to 5.5 % by weight of the solid formulation. The amounts of the niclosamide present in the solid formulation is applicable to any of the solid formulations described herein, for example a powder comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0033] The cyclodextrin may be o, b- or y-cyclodextrin, or a derivative thereof. In some embodiments, the cyclodextrin is b-cyclodextrin, or a derivative thereof. In some embodiments, the cyclodextrin is 2-hydroxypropyl- b -cyclodextrin (HR-b-CD). In some embodiments the cyclodextrin is sulfobutylether^-CD. In some embodiments the cyclodextrin is not sulfobutylether^-CD.

[0034] In some embodiments the cyclodextrin is present in an amount of about 1 % to about 90 % by weight of the formulation. For example, the cyclodextrin may be present in an amount of from about 5 % to about 85%, from about 10 % to about 80% or from about 20 % to about 70 % by weight, based on the weight of the formulation. [0035] In certain embodiments the cyclodextrin is present in an amount of about 1 % to about 60 % by weight of a liquid formulation. In certain embodiments the cyclodextrin is present in an amount of more than about 5%, more than about 6%, more than about 7%, more than about 8%, more than about 9%, more than about 10%, more than about 11%, more than about 12%, more than about 13%, more than about 14% or more than about 15% by weight of a liquid formulation. In certain embodiments the cyclodextrin is present in an amount of about 1 % to about 25 % by weight of a liquid formulation. For example, the cyclodextrin is present in an amount of 2 % to 24 %, 3 % to 23 %, 4 % to 22 %, 5 % to 21 %, 6 % to 20 %, 7 % to 19.5 %, 8 % to 19 %, 9 % to 18.5 %, 10 % to 18 %, 10.5 % to 17.5 %, 11 % to 17 %, 11.5 % to 16.5 %, 12 % to 16 %, 12.5 % to 15.5 %, 13 % to 15 % or 13.5 % to 14.5 %, by weight of the liquid formulation. In certain embodiments the cyclodextrin is present in an amount of about 10%, about 10.5%, about 11%, about 11.5%, about 12%, about 12.5%, about 13%, about 13.5%, about 14%, about 14.1%, about 14.2%, about 14.3%, about 14.4%, about 14.5%, about 14.6%, about 14.7%, about 14.8%, about 14.9%, about 15%, about 15.1%, about 15.2%, about 15.3%, about 15.4%, about 15.5%, about 15.6%, about 15.7%, about 15.8%, about 15.9%, about 16%, about 16.5% about 17%, about 17.5% or about 18%, by weight of the liquid formulation. For example, it may be that the cyclodextrin is HR-b-CD.

[0036] In a preferred embodiment the cyclodextrin is present in the liquid formulation in an amount of about 14.5 % to 15.5 % by weight of the liquid formulation. For example, it may be that HR-b-CD is present in the liquid formulation in an amount of about 14.5 % to 15.5 % by weight of the liquid formulation.

[0037] In certain embodiments the cyclodextrin is present in an amount of about 50 % to about 95 % by weight of a solid formulation. For example, the cyclodextrin may be present in an amount of from about 55 % to about 90 %, from about 60 % to about 85 %, from about 65 % to about 80 % or from about 70 % to about 75 % by weight, based on the weight of the solid formulation.

[0038] In some embodiments the liquid formulation comprises from about 0.1 % to about 1.5 % by weight of niclosamide ethanolamine and from about 10 % to about 20 % by weight of cyclodextrin (e.g. HR-b-CD).

[0039] In some embodiments the liquid formulation comprises from about 0.1 % to about 1.5 % by weight of niclosamide ethanolamine and from about 12 % to about 20 % by weight of cyclodextrin (e.g. HR-b-CD). In a preferred embodiment the liquid formulation comprises about 1 % by weight of niclosamide ethanolamine and about 15 % by weight of cyclodextrin (preferably HR-b-CD).

[0040] At least a portion of the niclosamide, or a pharmaceutically acceptable salt thereof may form a complex with the cyclodextrin. In some embodiments, from about 20 to about 100 %, from about 30 % to about 90%, from about 40 % to about 80% or from about 50 % to about 70% of the niclosamide, or a pharmaceutically acceptable salt thereof, is complexed with the cyclodextrin.

[0041] In some embodiments the weight ratio of niclosamide, or a pharmaceutically acceptable salt thereof, to cyclodextrin is from 1 :250 to 5: 1 , from 1 :200 to 4: 1 , from 1 : 150 to 3:1, from 1:100 to 2:1, from 1 :50 to 1:1, from 1:30 to 1 :2, from 1:20 to 1:3, from 1:20 to 1:8, from 1:20 to 1:12, from 1:18 to 1:12, from 1 :15 to 1:4 or from 1:10 to 1:5.

[0042] In some embodiments, the formulation comprises at least one stabilizer. Suitable stabilizers include polymers, emulsifiers, surfactants and combinations thereof. In some embodiments the stabilizer comprises a polymer. Suitably the polymer is a water soluble polymer, preferably a polymer that is soluble in water at the pH of the liquid formulations disclosed herein. Advantageously, the addition of a polymer may improve the stability of a solution comprising niclosamide, or a pharmaceutically acceptable salt thereof, and a cyclodextrin. Without being bound by theory, it is thought that the presence of the stabilizer (e.g. polymer) may aid complex formation between the niclosamide and cyclodextrin, and thus may also assist in preparing the formulation. Additionally or alternatively, the stabilizer (e.g. polymer) may help to inhibit crystallisation and subsequent precipitation of the solubilised niclosamide. Accordingly formulations comprising a stabilizer such as a polymer may provide high concentration of solubilised niclosamide in the formulation. The polymer may be selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinylalcohol (PVA), hydroxypropylcellulose (HPC), poloxamers, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC-AS ), polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA) and any combination thereof. Preferably, the polymer comprises PVP. As is known in the art, PVP is available in several viscosity grades, ranging from low to high molecular weight. Available PVP grades include K-12, K-15, K-17, K-30, K- 60, K-80, K-85, K-90 and K-120. In some embodiments, the formulation comprises PVP K- 12, K-15, K-17 or K-30. The K-value refers to the Fikentscher K value and may be determined by measuring the viscosity of a 1% wt./vol pf the PVP in water using Ostwald- Fenske or Cannon-Fenske capillary viscometer and calculating the K-value, for example using the method described in ISO 1628-1:2009. In some embodiments, the polymer is PVP/VA. As is known in the art, PVP/VA copolymers are available in different ratios of vinylpyrrolidone to vinyl acetate. The weight ratio of PVP : VA may be 70:30, 60:40, 50:50, 40:60 or 30:70. In some embodiments, the ratio is 60:40 (e.g. available as Kollidon® VA 64).

[0043] The polymer may be present in the formulation in an amount of from about 0.01 % to about 20 %, from about 0.05 % to about 18 %, from about 0.1 % to about 15 %, from about 0.5 % to about 13 %, from about 0.8% to about 12%, from about 1% to about 10%, from about 2 % to about 8% or from about 3 % to about 6 % by weight based on the weight of the formulation.

[0044] For example, the polymer may be present in a liquid formulation in an amount of from about 0.01 % to about 10 %, from about 0.05 % to about 8 %, from about 0.1 % to about 6 %, from about 0.1% to about 5%, from about 0.1% to about 4%, from about 0.1% to about 3%, from about 0.5% to about 5%, from about 0.5 % to about 4 %, from about 0.5% to about 3%, from about 0.8% to about 3%, from about 1% to about 4%, from about 1% to about 3%, from about 1 % to about 2.5%, or from about 1% to about 2% by weight based on the weight of the liquid formulation. Thus it may be that the polymer is present in a liquid formulation in an amount of about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1% about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2% about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.5%, about 4%, about 4.5% or about 5% by weight based on the weight of the liquid formulation.

[0045] The polymer may be present in a solid formulation in an amount of from about 1 % to about 20 %, from about 2 % to about 18 %, from about 3 % to about 16 %, from about 5 % to about 14 %, from about 5% to about 12%, from about 6% to about 11 %, from about 7 % to about 10 % or from about 8 to about 9 % by weight, based on the weight of the solid formulation.

[0046] In some embodiments the formulation further comprises a preservative. Suitable preservatives include benzalkonium chloride.

[0047] The preservative may be present in an amount of from about 0 to about 0.2 %, from about 0.002 % to about 0.15 %, from about 0.004 to about 0.1%, from about 0.006 % to about 0.05 %, or from about 0.008 % to about 0.02 % by weight (e.g. about 0.01 wt.%), based on the weight of the formulation. [0048] In some embodiments the formulation further comprises a buffer and/or a stabilising agent. Suitable buffers and stabilising agents include disodium edetate, disodium phosphate, polysorbate 80, sodium dihydrogen phosphate, sodium citrate, sodium phosphate, sodium acetate, acetic acid, histidine lactic acid, aspartic acid, tartaric acid, glutamic acid, succinic acid, malic acid, tromethamine, lactic acid, histidine, fumaric acid and citric acid. Preferably the stabilising agent comprises disodium edetate.

[0049] The stabilising agent may be present in an amount of from about 0 to about 2 % by weight, for example from about 0.02 % to about 1 %, from about 0.04 % to about 0.6 %, from about 0.06 % to about 0.4 %, or from about 0.08 % to about 0.2 % by weight (e.g. 0.1 wt.%), based on the weight of the formulation.

[0050] In some embodiments the formulation further comprises an electrolyte. Suitable electrolytes include sodium chloride, potassium chloride, sodium dihydrogen phosphate or potassium dihydrogen phosphate. Preferably the electrolyte is sodium chloride.

[0051] The electrolyte may be present in an amount of from about 0 % to about 10 %, from about 0.1 % to about 8 %, from about 0.2 % to about 5 %, from about 0.3 to about 2 %, from about 0.4 to about 1 %, or from about 0.5 to about 0.8 % by weight, based on the weight of the formulation.

[0052] In some embodiments the formulation has a viscosity of from 1 to 150 cP, from 1.5 to 100, from 2 to 50 cP or from 5 to 25 cP. In some embodiments, the formulation has a viscosity of no greater than 20, no greater than 15, or no greater than 10 cP. For example, the viscosity may be from 1 to 10, from 1.5 to 9.5, from 2 to 8, from 2.5 to 7.5, from 3 to 7, from 3.5 to 6.5, from 4 to 6 or from 5.5 to 6.5 cP.

[0053] In some embodiments the formulation has a pH of from 4 to 9, for example from 5 to 8.5, from 7 to 8.5, or from 6 to 8, e.g. from 4 to 8, from 7 to 8.2, from 7.5 to 8.2, from 7.5 to 7.8, or preferably from 7.6 to 8.

[0054] In some embodiments the formulation comprises a pH modifier. Suitable pH modifiers include acids (e.g. hydrochloric acid, acetic acid, lactic acid, citric acid, tartaric acid, malic acid, formic acid, uric acid) and bases (e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate). In some embodiments, the formulation comprises at multiple (e.g. 2, 3 or 4) pH modifiers. For example, the formulation may comprise two different acids, or two different bases, or an acid and a base. In some embodiments, the formulation comprises sodium hydroxide and hydrochloric acid. [0055] In some embodiments the formulation has an osmolarity of from 5 to 500 mOsmol/L, from 100 to 400 mOsmol/L, or from 150 to 350 mOsmol/L, for example from 180 to 320 mOsmol/L, from 250 to 350 mOsmol/L, from 280 to 330 mOsmol/L, from 290 to 320 mOsmol/L, or from 200 to 250 mOsmol/L.

[0056] In some embodiments the formulation comprises niclosamide. In some embodiments the composition comprises a pharmaceutically acceptable salt of niclosamide. In some embodiments the formulation comprises niclosamide ethanolamine.

[0057] In certain embodiments the viral infection in a subject may be caused by or associated with a virus selected from respiratory syncytial virus, influenza virus, parainfluenza virus, human metapneumovirus, severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), a human rhinovirus (HRVs) and human adenovirus (HAdV).

[0058] In certain embodiments the viral infection is caused by or associated with a Pneumoviridae virus, for example a Human respiratory syncytial virus (HRSV) (e.g. HRSV- A2, HRSV-B1 or HRSV-S2).

[0059] In certain embodiments the viral infection is caused by or associated with a Coronaviridae virus. In certain embodiments the viral infection is caused by or associated with a virus is selected from Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus. Preferably the viral infection is caused by or associated with a Betacoronavirus. Thus is certain embodiments the viral infection is caused by or associated with a virus is selected from severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), HCoV-229E, HCoV-NL63, HCoV-OC43 and HCoV- HKU1.

[0060] In a particular embodiment the viral infection is caused by or associated with SARS- CoV-2. This it may be that the viral infection is COVID-19.

[0061] In some embodiments the viral infection is caused by or associated with an influenza virus.

[0062] The formulation is administered intranasally. It will be understood that “intranasal” administration means administration into the nasal cavity, i.e. through the nose. Intranasal administration encompasses both administration of the formulation to the nasal mucosa and the upper respiratory tract, and administration of the formulation to the lower respiratory tract (e.g. via inhalation). In certain embodiments, the formulation is administered intranasally in the form of, droplets or as a spray. The formulation is suitably administered intranasally using an intranasal delivery device, for example using a metered dose nasal pump device.

[0063] Recent research has identified a gradient of expression levels of the human angiotensin-converting enzyme (ACE)-2, which is targeted by SARS-CoV-2, from the nasal tissues (high expression) and the distal intrapulmonary regions (low expression). This expression pattern was found to be mirrored by a gradient of SARS-CoV-2 infectivity which was high in the nasal epithelium and markedly reduced in the distal lung (bronchioles, alveoli). In light of these findings, it has been suggested that the nasal surfaces may be the dominant initial site of SARS-CoV-2 infection (Hou et al., “SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract”, Cell, 2020). Intranasal administration may therefore be beneficial to subjects suffering from mild COVID-19, or those in the early stages of disease, prior to progression to the later stages of the disease which are characterised by pulmonary inflammation. In some embodiments, subjects whose symptoms include a loss of taste and/or smell, and/or ocular symptoms (e.g. one or more of conjunctival hyperemia, chemosis, epiphora, or increased secretions) may be treated via intranasal administration of the formulation. Intranasal administration may also be beneficial for treating asymptomatic subjects, for prophylactic treatment of high risk populations as identified herein.

[0064] The niclosamide, or a pharmaceutically acceptable salt thereof, may be administered to the subject in a unit dosage of from about 10 mg to about 1000 mg based on the weight of the niclosamide, or pharmaceutically acceptable salt thereof (for example from about 100 mg to about 600 mg, preferably about 150 mg to about 500 mg, based on the weight of the niclosamide, or pharmaceutically acceptable salt thereof.

[0065] The niclosamide, or a pharmaceutically acceptable salt thereof, may be administered to the subject one to five times per day, for example from 1 to 4 times per day, e.g. 2 or 3 times per day.

[0066] The formulation may be administered as a unit dosage comprising a solution of niclosamide, or a pharmaceutically acceptable salt thereof, and a cyclodextrin, wherein the niclosamide is present in an amount of from about 0.1 mg to about 200 mg, for example from about 0.5 mg to about 100 mg or from about 1 mg to about 50 mg, based on the weight of the niclosamide. The solution may be any of the solutions comprising niclosamide, or a pharmaceutically acceptable salt thereof, and a cyclodextrin as described herein. For example, the solution may be any of the solutions comprising niclosamide ethanolamine and a cyclodextrin (e.g. HR-b-CD) as disclosed herein. Suitably the solution is an aqueous solution. The unit dosage is suitably present in a container, for example a vial, blister pack, bottle (e.g. a nasal spray), or syringe (e.g. as part of an intranasal delivery device). In embodiments wherein the formulation is in the form of a solution, the unit dosage volume administered to the subject may be from 1 to 15 ml, from 1 to 10 ml_, from 7 to 9 ml_, from 2 to 9 ml, from 3 to 8 ml or from 4 to 6 ml. In some embodiments, the unit dosage volume administered to the subject is from 10 mI to 10 ml, from 20 pi to 8 ml, from 30 mI to 6 ml, from 40 mI to 5 ml, from 50 mI to 2 ml, from 100 mI to 1 ml, from 120 mI to 0.8 ml, from 130 mI to 0.7 ml, from 140 mI to 0.6 ml, from 150 mI to 0.5 ml or from 200 mI to 400 mI. In some embodiments, the unit dosage volume administered to the subject is from 100 to 200 mI, from 110 to 190 mI, from 120 to 180 mI, from 130 to 170 mI, from 140 to 160 mI or from 150 to 155 mI. It will be appreciated that the mass of the niclosamide, or a pharmaceutically acceptable salt thereof, administered for a given volume will depend on the concentration of the solution. In some embodiments, the niclosamide, or a pharmaceutically acceptable salt thereof, is present in the solution in an amount of from about 0.01 % to about 10 % by weight. Preferably the solution comprises about 1 % by weight of niclosamide ethanolamine. The volume may be administered one or more times per day, for example once per day, twice per day, three times per day or four times per day. It may be that the volume is administered once or twice per day. It may be that the volume is administered once per day. It may be that the volume is administered twice per day.

[0067] In some embodiments wherein the formulation is a solution, the volume administered intranasally to the subject may be from 50 to 500 mI, from 100 to 400 mI, from 150 to 300 mI or from 200 to 250 mI. It will be appreciated that approximately half of the volume should be administered to each nostril. In some embodiments, from about 50 to about 150 mI is administered to each nostril (i.e. about 100 to about 300 mI in total). In some embodiments, a volume of about 130 mI-150 mI (e.g. 140 mI) is administered to each nostril (i.e. about 260- 300 mI, e.g. 280 mI, in total). Preferably the solution administered intranasally comprises about 1 % by weight of niclosamide ethanolamine. The volume may be administered intranasally one or more times per day, for example once per day, twice per day, three times per day or four times per day. It may be that the volume is administered intranasally once or twice per day. It may be that the volume is administered intranasally once per day. It may be that the volume is administered intranasally twice per day.

[0068] The formulation may be intranasally administered to the subjects using a kit comprising a container comprising the formulation comprising niclosamide, or a pharmaceutically acceptable salt thereof, and the cyclodextrin; and an intranasal delivery device.

[0069] Embodiments of the invention will now be described by way of example and with reference to the accompanying Figures, in which:

Figure 1 is a graph showing the epithelial lining fluid (ELF) concentration of niclosamide free base following pulmonary administration in sheep compared to systemic exposure of highest human oral dose, relative to IC90 against SARS-CoV-2. (A) Mean ELF concentration of niclosamide over time following pulmonary administration (± SEM); (B) Comparison of mean Cmax levels of niclosamide (“UN 1911 ”) in ELF to systemic Cmax following a 2 g/day oral dose in humans (Data of Andrews et al. 1983, Pharmacology & therapeutics, 19(2), 245-295 (healthy volunteers) and Burock et al. 2018, BMC Cancer, 18(1): 297 (colorectal cancer patients) combined in “2000 mg single/qd” column);

Figure 2 are plots showing the pharmacokinetic profile of niclosamide ethanolamine per cohort in the phase 1 clinical trial described in Example 8; and

Figure 3 is a comparison of systemic exposure (Cmax; mean ± SEM) of niclosamide administered orally versus inhalation in humans. No mean for “2000 mg, single” column generated as only range of Cmax reported in literature. Data for 500-1000 mg obtained from Schweizer et al., 2018, PLoS ONE.;13(6): e0198389. Data for 2000 mg obtained from Andrews et al. 1983 and Burock et al. 2018 (as above);

Figure 4 shows a correlation plot of systemic exposure (Cmax-, mean ±) of human versus sheep study.

DETAILED DESCRIPTION Definitions

[0070] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0071] The terms “treating” or “treatment” refer to any indicia of success in the treatment or amelioration of a disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the pathology or condition more tolerable to the subject; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving the physical or mental well being of the subject. For example, in relation to the treatment of a respiratory viral infection disclosed herein the treatment may include one or more of the following: Reduce or eliminate the virus; prevent or reduce viral replication; reduce or eliminate transmission of the infection; reduce or eliminate fever; reduce or eliminate flu-like symptoms, reduce or eliminate coughing, reduce or eliminate muscle and/or joint pain; improve respiratory status of the subject (e.g. increasing blood oxygen saturation; reducing or eliminating the requirement for oxygen therapy); an improvement in the NEWS2 score; the prevention or treatment of acute respiratory distress syndrome, e.g. associated with the viral infection; the treatment or prevention of pneumonia associated with the viral infection; the treatment or prevention of viral pneumonia; the treatment or prevention of bacterial pneumonia associated with a viral infection; reducing or eliminating pulmonary edema; reducing or eliminating pulmonary inflammation; preventing or reducing lung fibrosis (e.g. preventing or reducing interstitial fibroblasts); reducing one or more inflammatory biomarkers associated with the respiratory viral infection. In some embodiments the terms “treating” or “treatment” refer to prophylactic treatments, wherein a subject is treated with the formulation to prevent or reduce the risk of a subject contracting a respiratory viral infection, or to prevent a respiratory viral infection from becoming symptomatic. It is appreciated that the methods disclosed herein may also be used in the treatment of asymptomatic subjects.

[0072] The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease (e.g. a viral infection such as SARS- CoV-2) means that the disease is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function.

The term ”SARS-CoV-2” means severe acute respiratory syndrome coronavirus that causes the COVID-19 disease. An example of a nucleotide sequence of a SARS-CoV-2 virus is described by Wu et al. (Nature 579, 265-269 (2020) (Genbank accession no. MN908947.3, isolate Wuhan-Hu-1). The subject may be infected with a SARS-CoV-2 virus having a genome sequence which is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%, at least 99.91%, at least 99.92%, at least 99.93%, at least 99.94%, at least 99.93%, at least 99.95%, at least 99.96%, at least 99.97%, at least 99.98%, or at least 99.99% identical to MN908947.3. The treatment or prophylaxis of any variant of SARS-CoV-2 is encompassed by the invention. No single consistent nomenclature currently exists for SARS-CoV-2 strains, although a number of nomenclatures have been proposed. In some embodiments, the SARS-CoV-2 variant belongs to one of clades S, O, L, V, G, GH, GR or GV (as defined by GISAID “Global phylogeny, updated by Nextstrain”). In some embodiments, the SARS- CoV-2 variant belongs to one of clades 19A, 19B, 20A, 20B, 20C, 20D, 20E, 20F, 20G, 20H or 201 (clades.nextstrain.org, archived in Wayback machine on 19 January 2021). In some embodiments, the SARS-CoV-2 variant belongs to one of the lineages A, B, B.1 , B1.1 , B1.177 or B.1.1.7 (as proposed by Rambaut etal., Nature Microbiology volume 5, pages 1403-1407(2020)). In some embodiments, the SARS-CoV-2 variant is selected from the group consisting of: the 501 M2 variant (also known as 501 V2, 20H/501Y.V2 (formerly 20C/501 Y.V2), VOC-202012/02 (PHE), lineage B.1.351 or “The South African variant”); Cluster 5 (also referred to as AFVI-spike by the Danish State Serum Institute (SSI), believed to have spread from minks); Lineage B.1.1.207; Lineage B.1.1.7 / Variant of Concern 202012/01 (see Chand et al., “Investigation of novel SARS-COV-2 variant, Variant of Concern 202012/01, Public Health England); Lineage B.1.429 / CAL.20C; Lineage B.1.525 (also called VUI-202102/03 by Public Health England (PHE) and formerly known as UK1188); Lineage P.1 (also called Variant of Concern 202101/02 by Public Health England and 20J/501Y.V3 by Nextstrain), Lineage P.1 (also known as “Gamma”), Lineage B.1.617.2 (also known as “Delta”), and Lineage B.1.1.529 (also known as “Omicron”).

[0073] When a compound or salt (e.g. niclosamide or a pharmaceutically acceptable salt thereof) described in this specification is administered to treat a disorder, a “therapeutically effective amount” is an amount sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder; cure the disorder; reverse, completely stop, or slow the progress of the disorder; or reduce the risk of the disorder getting worse.

[0074] The term “pharmaceutically acceptable salt” refers to salts that retain the biological effectiveness and properties of the compounds described herein and, which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts of niclosamide are well known to skilled persons in the art. Particular niclosamide salts include ethanolamine or piperazine salts. Accordingly, it may be that a reference to a salt of niclosamide herein may refer to a pharmaceutically acceptable salt of niclosamide, in particular an ethanolamine salt of niclosamide (also referred to herein as niclosamide ethanolamine) (e.g. the 1:1 salt of niclosamide with 2-aminoethanol).

[0075] Reference to the formulation being in the form of a “solution” means that the components of the formulation are sufficiently dissolved such that the formulation is clear to the naked eye (i.e. the formulation is free from visible particles).

[0076] Reference to a “subject” herein means a human or animal subject. Preferably the subject is warm-blooded mammal. More preferably the subject is a human. In all cases the subject is selected from a subject undergoing dialysis, a kidney transplant recipient and a subject with vasculitis, an auto-immune kidney disease or glomerulonephritis. [0077] Unless stated otherwise, reference herein to a “% by weight of niclosamide, or a pharmaceutically acceptable salt thereof is intended to refer to the amount of the free acid (i.e. non-salt form) of the niclosamide. For example, reference to a composition comprising “5% by weight of niclosamide, or a pharmaceutically acceptable salt thereof” refers to a composition comprising 5% by weight of the niclosamide as the free acid. Accordingly, where such a composition comprises a pharmaceutically acceptable salt of niclosamide, the absolute amount of the salt in the composition will be higher than 5% by weight in view of the salt counter ion that will be also be present in the composition.

[0078] Reference to a “non-aqueous” composition, means that the composition is anhydrous and therefore substantially water free. For example, the compositions disclosed herein (e.g. solutions or suspensions comprising niclosamide, or a pharmaceutically acceptable salt thereof) contain less than 5%, less than 1% or suitably less than 0.01%, preferably less than 0.001% by weight water. Preferred non-aqueous compositions are those which are anhydrous and contain no detectable water.

[0079] Where reference is made herein to the formulation for use in the treatment or prevention of a respiratory viral infection is to be understood as also encompassing a method for the treatment or prevention of that condition in a subject by intranasally administering an effective amount of the formulation to the subject; and use of the formulation for the manufacture of a medicament for the intranasal treatment or prevention of the condition.

[0080] Reference to “about” in the context of a numerical is intended to encompass the value +/- 10%. For example, about 20% includes the range of from 18% to 22%.

[0081] Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0082] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0083] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

Cyclodextrins

[0084] Cyclodextrins are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of five or more glucose subunits joined by a-1 ,4 glycosidic bonds. Common cyclodextrins having six to eight glucose units include: a-cyclodextrin (six glucose units), b- cyclodextrin (seven glucose units) and y-cyclodextrin (eight glucose units). Derivatives of cyclodextrins may be prepared by chemical modification of some or all of the hydroxyl groups, for example by the addition of alkyl (e.g. methyl, hydroxypropyl or hydroxyethyl) or acetyl groups. Cyclodextrin may be chemically modified in order to improve its solubility.

[0085] In some embodiments, the cyclodextrin is water soluble. A water-soluble cyclodextrin derivative preferably used in the present invention refers to a derivative having water solubility of at least that of b-cyclodextrin. Examples of such water-soluble cyclodextrin derivatives are sulfobutylcyclodextrin, hydroxypropylcyclodextrin, maltosylcyclodextrin, and salts thereof. In particular, sulfobutyl^-cyclodextrin, hydroxypropyl^-cyclodextrin, maltosyl- b-cyclodextrin, and salts thereof.

[0086] Other preferred cyclodextrin derivatives according to the invention are methylcyclodextrins (products of the cyclodextrins methylation), dimethylcyclodextrins (DIMEB) (preferably substituted in 2 and in 6), trimethylcyclodextrins (preferably substituted in 2, 3 and 6), "random methylated" cyclodextrins (RAMEB) (preferably substituted at random in 2, 3 and 6, but with a number of 1 ,7 to 1 ,9 methyl by unit glucopyrannose), hydroxypropylcyclodextrins (HPCD, hydroxypropylated cyclodextrins preferably substituted randomly mainly in position 2 and 3 (e.g. HR-b-CD, HR-g-CD)), sulfobutylethercyclodextrins (SBECD), hydroxyethyl-cyclodextrins, carboxymethylethylcyclodextrins, ethylcyclodextrins, cyclodextrins amphiphiles obtained by grafting hydrocarbonated chains in the hydroxyl groups and being able to form nanoparticles, cholesterol cyclodextrins and triglycerides- cyclodextrins obtained by grafting cyclodextrins monoaminated (with a spacer arm).

[0087] The cyclodextrin may be or a derivative thereof, such as methylated, acetylated or hydroxypropylated a-cyclodextrin. The cyclodextrin may be b-cyclodextrin or a derivative thereof, such as methylated, acetylated and/or hydroxypropylated b-cyclodextrin. The cyclodextrin may be or y-cyclodextrin or a derivative thereof, such as such as methylated, acetylated and/or hydroxypropylated g-cyclodextrin. In some embodiments, the cyclodextrin is selected from the group consisting of: beta-cyclodextrin and its synthetic derivatives such as HR-b-CD, SBE^-CD, RM^-CD, DIME^-CD, TRIME^-CD, hydroxybutyl^-CD, glucosyl- b-CD, and maltosyl^-CD. In some embodiments, the cyclodextrin is selected from the group consisting of: g-cyclodextrin and its synthetic derivatives such as HR-g-CD, SBE-y-CD, RM-y-CD, DIME-y-CD, TRIME-y-CD, hydroxybutyl-y-CD, glucosyl-y-CD, and maltosyl-y-CD.

[0088] Preferably the cyclodextrin is HR-b-CD.

Solutions and suspensions comprising niclosamide, or a pharmaceutically acceptable salt thereof and a cyclodextrin

[0089] In certain embodiments the formulation comprising niclosamide, or a pharmaceutically acceptable salt thereof, and a cyclodextrin is a solution or suspension. Preferably the solution or suspension is a liquid, more preferably a liquid that is suitable for aerosolization using for example a nebulizer inhaler. Thus a reference herein to any of the solutions or suspensions comprising niclosamide, or a pharmaceutically acceptable salt thereof, and a cyclodextrin are preferably liquid solutions or liquid suspensions comprising the niclosamide, or a pharmaceutically acceptable salt thereof, and a cyclodextrin.

[0090] In certain embodiments the niclosamide, or a pharmaceutically acceptable salt thereof, and the cyclodextrin are dissolved or dispersed in a liquid medium to provide a solution or suspension suitable for intranasal administration. In certain embodiments the niclosamide, or a pharmaceutically acceptable salt thereof, and a cyclodextrin are dissolved or dispersed in a solvent comprising or consisting of water, thereby forming an aqueous solution or suspension. In some embodiments, the niclosamide, or a pharmaceutically acceptable salt thereof, and a cyclodextrin are dissolved or dispersed in a solvent comprising water and a co-solvent.

[0091] It has been found that some niclosamide formulations are able to form a substantially clear solution, i.e. with no visible precipitate. Thus, in some embodiments a solution administered to the subject is substantially clear. In some embodiments, the solution is physically stable (i.e. no visible precipitate forms) when stored (e.g. in a closed container) for at least 1 day, at least 2 days, at least 4 days, at least 7 days, at least 14 days, at least 21 days or at least 28 days. The solution may be physically stable when stored (e.g. in a closed container) at 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C or 40°C. In some embodiments, the solution is physically stable after storage (e.g. in a closed container) at 25°C for at least 7, 14 or 28 days. In some embodiments, the solution is physically stable after storage (e.g. in a closed container) at 40°C for at least 7, 14 or 28 days.

[0092] In embodiments where the niclosamide, or a pharmaceutically acceptable salt thereof, and the cyclodextrin are present as a suspension in a liquid medium niclosamide, or a pharmaceutically acceptable salt thereof, may be present in the solution or suspension in the liquid medium in any of the amounts described herein. When the niclosamide, or pharmaceutically acceptable salt thereof is present as a solution, the solution typically contains from about 0.1 to about 5 % by weight (e.g. about 1 %) of the niclosamide, or pharmaceutically acceptable salt thereof.

[0093] The cyclodextrin may be present in the solution or suspension in the liquid medium in any of the amounts described herein. When the cyclodextrin is present as a solution, the solution typically contains from about 1 to about 60 %, by weight, for example about 1 to about 25 % by weight (e.g. about 15 %) of the cyclodextrin.

[0094] Niclosamide is known to be poorly soluble in water. Without being bound by theory, it is thought that at least a portion of the niclosamide will form a complex with the cyclodextrin in the formulation, thereby improving its solubility. In particular, complexation with cyclodextrin is believed to be beneficial for the intranasal treatment of a respiratory viral infection, since the complex may help to prevent precipitation of the niclosamide when the formulation contacts the intranasal and upper respiratory tract tissues. It will be appreciated that in solution or suspension the niclosamide and cyclodextrin may continuously fluctuate between a bound (i.e. complexed) and non-bounded (i.e. non-complexed) state. Thus, from about 20 to about 100 % by weight of the niclosamide may form a complex with the cyclodextrin, based on the weight of the niclosamide. In liquid formulations, any non- complexed components (niclosamide and/or cyclodextrin) may be present in solution and/or suspension.

[0095] Liquid formulations comprising niclosamide, or a pharmaceutically acceptable salt thereof and a cyclodextrin administered to the subject may have an osmolality from about 100 mOsmol/kg to about 1000 mOsmol/kg. In some embodiments, the osmolality is from about 150 mOsmol/kg to about 750 mOsmol/kg, from about 200 mOsmol/kg and about 500 mOsmol/kg, preferably from about 230 to about 350 mOsmol/kg, more preferably from about 280 to about 330 mOsmol/kg (e.g. from about 290 to about 320 mOsmol/kg).

[0096] In some embodiments, a liquid formulation comprises from about 1 % to about 25 % by weight of cyclodextrin and from about 0.1 % to about 5 % by weight of niclosamide or a pharmaceutically acceptable salt thereof (e.g. niclosamide ethanolamine), based on the weight of the liquid formulation.

[0097] In some embodiments, a liquid formulation comprises:

0.1-5 % of a niclosamide, or a pharmaceutically acceptable salt thereof, for example 0.5-2 % or 1-1.5 % of niclosamide ethanolamine;

1-25% of cyclodextrin, for example 3-15% or 5 to 10% of HR-b-CD;

0.1-10% of polymers, for example 0.5-5% or 1-2 % of PVP;

0-0.2% of stabilizing agent, for example 0.05 to 0.1 % of disodium edetate;

0-0.02% of preservative, for example 0.005-0.01 % benzalkonium chloride.

0-0.9% of electrolyte, for example 0.1-0.5 % of sodium chloride;

0-10% of a co-solvent, for example 0.5-5% or 1% of DMSO; the balance being water, wherein the percentages are by weight based on the weight of the liquid formulation.

Suitably the liquid formulation has a pH of from 7.0 to 8.5, for example from 7.5 to 7.8, or from 7.6 to 8.0, preferably about 7.8.

[0098] In some embodiments, a liquid formulation comprises:

0.1-5 % of niclosamide or a pharmaceutically acceptable salt thereof, for example 0.5-2 % or 1-1.5 % of niclosamide ethanolamine;

1-25% of cyclodextrin, for example 3-15% or 5 to 10% of HR-b-CD;

0.1-10% of polymers, for example 0.5-5% or 1-2 % of PVP;

0- 3% of one or more pH modifiers(suitably the pH modifiers are present in an amount to provide a pH of from 7.0 to 8.5, for example from 7.5 to 7.8, or from 7.6 to 8.0, preferably about 7.8. For example 0.1 -0.5% of NaOH (e.g. added as a solid or a 1 M solution), and 0.5- 3.0% of 2N HCI); the balance being water, wherein the percentages are by weight based on the weight of the liquid formulation.

[0099] In some embodiments, a liquid formulation comprises:

0.5-1.5 % niclosamide ethanolamine; 5-20% cyclodextrin, preferably a b-cyclodextrin, more preferably HR-b-CD;

0.5-5% PVP (e.g. PVP 30); the balance being water, wherein the percentages are by weight based on the weight of the liquid formulation; and wherein the formulation has a pH of from 7.0 to 8.5, for example from 7.5 to 7.8, or from 7.6 to 8.0, preferably about 7.8.

[00100] In some embodiments, a liquid formulation comprises: about 1 % niclosamide ethanolamine; about 15% cyclodextrin, preferably a b-cyclodextrin, more preferably HR-b-CD; about 2% PVP (e.g. PVP 30); the balance being water, wherein the percentages are by weight based on the weight of the liquid formulation; and wherein the formulation has a pH of from 7.0 to 8.5, for example from 7.5 to 7.8, or from 7.6 to 8.0, preferably about 7.8. [00101] In some embodiments, a liquid formulation comprises: about 1 % niclosamide ethanolamine; about 10% cyclodextrin, preferably a b-cyclodextrin, more preferably HR-b-CD; about 2% PVP (e.g. PVP 30); the balance being water, wherein the percentages are by weight based on the weight of the liquid formulation; and wherein the formulation has a pH of from 7.0 to 8.5, for example from 7.5 to 7.8, or from 7.6 to 8.0, preferably about 7.8.

[00102] In certain embodiments intranasal administration of the formulation delivers the niclosamide to the upper respiratory tract for example one or more of the nose and nasal passages, paranasal sinuses, the pharynx, the portion of the larynx above the vocal cords.

Other Components in Inhalable Pharmaceutical Compositions

[00103] The formulation comprising niclosamide and a cyclodextrin described herein optionally further comprise one or more viscosity modifying agents, emulsifiers, surfactants, humectants, oils, waxes, polymer, preservatives, pH modifying agents (for example a suitable acid or base, for example an organic acid or organic amine base), buffers, stabilizers, electrolytes antioxidants (for example butylated hydroxyanisol or butylated hydroxytoluene), crystallisation inhibitors (for example a cellulose derivative such as hydroxypropylmethyl cellulose or polyvinylpyrrolidone), colorants, fragrances and taste- masking agents. Such excipients s are well-known, for example as listed in the Handbook of Pharmaceutical Excipients, 7^th Edition, Rowe et al.

Systems and devices Intranasal delivery devices

[00104] The formulation may be intranasally administered to the subject using an intranasal delivery device. The intranasal delivery device may be adapted to deliver a solution or suspension to the nasal mucosa. The intranasal delivery device may be a dropper, a metered dose spray pump (e.g. a multi-dose, or a bi-directional multidose spray pump), a squeeze bottle, a single-dose or duo-dose spray device, a nasal pressurized metered-dose inhaler (pMDI), a pulsation membrane nebulizer, a nasal sonic/pulsating jet nebulizer, a vibrating mesh nebulizer, a nasal atomizer or a gas- or electrically-driven atomizer.

[00105] Squeeze bottles are generally used to deliver over-the-counter medicines, such as decongestants. By manually squeezing a deformable (e.g. plastic) air-filled bottle, the solution is atomized when delivered through a jet outlet.

[00106] Metered-dose spray pumps are commonly used for nasal drug delivery. Traditional spray pumps use preservatives to prevent contamination when the emitted liquid is replaced with air. However, more recent devices avoid the need for preservatives by using a collapsible bag, a moveable piston or a compressed gas to replace the emitted liquid, or alternatively use a filter to decontaminate the air. Commercially available nasal spray pumps are sold by Aptar Group.

[00107] Single-dose or duo-dose spray devices are intended for one-off or sporadic use, and/or where accurate dosing is important, for example for the administration of expensive drugs and vaccines. Commercially available devices include the MAD Nasal™ Intranasal Mucosal Atomization Device, and the Accuspray™ sold by Becton Dickinson Technologies.

[00108] Nasal pressurized metered-dose inhalers (pMDIs) have been developed which use hydrofluoroalkanes (HFAs) as a propellant. Such devices have been approved for the treatment of allergic rhinitis. [00109] Pulsation membrane nebulizers generate an aerosol via a perforated vibrating membrane. Commercially available devices include the VibrENT device sold by PARI Pharma GmbH. Other types of commercially available nebulizers and atomizers include the Atomisor NL11S^® sonic (a nasal sonic/pulsating jet nebulizer, DTF-Medical, France) the Aeroneb Solo^® (a mesh nebulizer, Aerogen), OptiNose® devices comprising Bi-Directional™ technology, the ViaNase™ electronic atomizer (Kurve Technology Inc.) and nitrogen-driven atomizers (e.g. as sold by Impel Inc.).

[00110] In some embodiments, the intranasal delivery device is adapted to deliver a powder to the nasal mucosa. The intranasal delivery device may be a nasal powder inhaler (e.g. which is adapted for nasal delivery), a nasal powder sprayer or a nasal powder insufflator. Commercially available devices include Rhinocort Turbuhaler®, Twin-lizer™, Fit-lizer™ (SNBL), Unidose™ Xtra (Bespak), Monopowder (Aptar group), and the powder Exhalation Delivery System (EDS) sold by OptiNose®.

Container

[00111] In some embodiments, liquid formulations as described herein are intranasally administered using a dropper bottle. In some embodiments, a dropper bottle comprising a squeezable container is provided with a tapered dispenser that terminates in a discharge aperture.

[00112] Alternatively, liquid dispensers have been developed in which the formulation is supplied from a storage bottle through a dropper, for example (dropper bottles or EDO- Ophthiols). The aqueous formulation, in some embodiments, flows out of the dropper opening as a result of manual pressure being applied to the compressible storage bottle.

[00113] In some embodiments, the formulations as described herein are stored in a plastic or glass bottle. In some embodiments, the plastic bottle is a low-density polyethylene bottle. In some embodiments, the formulation described herein is stored in a glass bottle with or without a liquid dispenser. In some embodiments, the plastic or glass bottle is opaque.

Viral infections

[00114] Viruses which infect or which carry out at least one phase of their life cycle or are pathogenic in the respiratory tract are of most interest in the present invention. Such viruses can in some cases enter a subject via the respiratory tract (e.g. they are capable of transmission through inhalation, e.g. via airborne or droplet transmission), and/or they may carry out initial or further stages of replication in the respiratory tract (e.g. upper or lower respiratory tract). Some well-known examples of viruses that are transmitted through airborne or droplet transmission include coronaviruses, influenza virus, parainfluenza virus, adenoviruses, respiratory syncytial virus, human metapneumovirus. Other viruses not considered classical airborne or droplet transmitted virus can in some circumstances be transmitted through the air, e.g. is bodily fluids containing the virus are aerosolised. Furthermore, other viruses that are not transmitted through the air may replicate or be pathogenic in the respiratory tract, and thus can be treated using the inhalable composition described herein.

[00115] Viruses that are transmitted through airborne or droplet transmission and/or which cause viral respiratory disease are of particular interest in the present invention.

[00116] The formulations of the invention are administered intranasally to provide the treatment or prevention of a respiratory viral infection. The viral infection is caused by or associated with a respiratory virus. Thus it may be that the viral infection is a respiratory tract infection. The viral infection may be an upper respiratory tract infection. The viral infection may be a lower respiratory tract infection, for example a viral infection affecting the lungs.

[00117] In some embodiments, the viral infection is caused by or associated with a virus selected from respiratory syncytial virus, influenza virus, parainfluenza virus, human metapneumovirus, coronavirus (e.g. severe acute respiratory syndrome coronavirus (SARS- CoV), severe acute respiratory syndrome coronavirus (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV)), a human rhinovirus (HRVs), human adenovirus (HAdV)

[00118] In some embodiments, the respiratory viral infection is a respiratory tract infection (RTI). A respiratory tract infection (RTI) is an infectious diseases involving the respiratory tract. An infection of this type is normally further classified as an upper respiratory tract infection (URI or URTI) or a lower respiratory tract infection (LRI or LRTI). The RTI can be an upper or lower RTI. Lower respiratory infections, such as pneumonia, tend to be far more serious conditions than upper respiratory infections, such as the common cold. The upper respiratory tract is generally considered to be the airway above the glottis or vocal cords, sometimes it is taken as the tract above the cricoid cartilage. This part of the tract includes the nose, sinuses, pharynx, and larynx. Symptoms of URIs can include cough, sore throat, runny nose, nasal congestion, headache, low grade fever, facial pressure and sneezing. The lower respiratory tract consists of the trachea (wind pipe), bronchial tubes, the bronchioles, and the lungs. Lower respiratory tract infections are generally more serious than upper respiratory infections. LRIs are the leading cause of death among all infectious diseases. The two most common LRIs are bronchitis and pneumonia.

[00119] The virus can be a RNA virus or a DNA virus. In certain embodiments the viral infection is caused by or associated with an RNA virus. In certain embodiments the viral infection is caused by or associated with a DNA virus. In certain embodiments the viral infection is caused by or associated with a positive-sense strand RNA virus.

[00120] In certain embodiments the respiratory viral infection is caused by or associated with a virus selected from respiratory syncytial virus, influenza virus, parainfluenza virus, a pneumovirus ( e.g. human metapneumovirus), a coronavirus (e.g. severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus (SARS- CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV)), human rhinovirus (HRVs), human adenovirus (HAdV).

[00121] In some embodiments the respiratory virus is an RNA virus that causes or is associated with a RTI.

[00122] In some embodiments the respiratory viral infection can cause or may be associated with acute respiratory syndrome, e.g. severe acute respiratory syndrome (SARS). Viruses which are known to cause severe acute respiratory syndrome (SARS) include coronaviruses such as a SARS viruses or MERS viruses, e.g. SARS-CoV, SARS- CoV-2 or MERS-CoV. In one embodiment the respiratory viral infection causes SARS.

[00123] The viruses of the Pneumoviridae family are negative sense, single-stranded, RNA viruses. Two genera within the Pneumoviridae family are Metapneumo virus and Orthopneumovirus. Particular species of Metapneumovirus are avian metapneumovirus (AMPV) and human metapneumovirus (HMPV). Particular species of Orthopneumovirus are Bovine respiratory syncytial virus (BRSV), Human respiratory syncytial virus (HRSV) and Murine pneumonia virus (MPV). Viruses in the Pneumoviridae family are typically transmitted through respiratory secretions and are often associated with respiratory infections. In certain embodiments the viral infection is caused by or associated with Human respiratory syncytial virus (HRSV). Thus it may be that the virus is caused by or associated with a virus selected from: HRSV-A2, HRSV-B1 and HRSV-S2.

[00124] Coronaviridae viruses are a family of enveloped, positive-stranded, single-stranded, spherical RNA viruses. The Coronaviridae family includes two sub-families, Coronavirus and Torovirus. The Coronavirus genus has a helical nucleocapsid, and Torovirus genus has a tubular nucleocapsid. Within the Coronavirus sub-family are the following genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus. Genera within the Torovirus sub-family are Bafinivirus and Torovirus. In certain embodiments the viral infection is caused by or associated with a coronavirus. Thus is may be that the viral infection is caused by or associated with a virus selected from Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus. In a preferred embodiment the viral infection is caused by or associated with a Betacoronavirus.

[00125] Human coronaviruses usually cause mild to moderate upper-respiratory tract illnesses, like the common cold, that last for a short amount of time (although some coronaviruses can be deadly). Symptoms may include runny nose, cough, sore throat, and fever. These viruses can sometimes cause lower-respiratory tract illnesses, such as pneumonia. This is more common in people with cardiopulmonary disease or compromised immune systems, or the elderly.

[00126] In some embodiments, the viral infection is a common cold. The common cold may be caused by or associated with a virus selected from respiratory syncytial virus (RSV), parainfluenza virus, a pneumovirus ( e.g. human metapneumovirus), a coronavirus, rhinovirus (e.g. human rhinovirus, HRVs), adenovirus (e.g. human adenovirus, HAdV), and enterovirus.

[00127] Middle East respiratory syndrome coronavirus (MERS-CoV) is a member of the Betacoronavirus genus, and causes Middle East Respiratory Syndrome (MERS). MERS is an acute respiratory illness. About half of the individuals confirmed to have been infected with MERS died. There is no current treatment or vaccine for MERS.

[00128] Another member of the Betacoronavirus genus is SARS coronavirus (SARS-CoV). SARS-Co-V is the virus that causes severe acute respiratory syndrome (SARS). SARS was first reported in Asia in February 2003. SARS is an airborne virus, and can spread by the inhalation of small droplets of water that an infected individuals releases into the air (for example, by coughing and/or sneezing), touching a contaminated surface and/or by being in close proximity of an infected individual.

[00129] In certain embodiments the viral infection is caused by or associated with severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS- CoV), HCoV-229E, HCoV-NL63, HCoV-OC43 and HKU1.

[00130] In certain embodiments the viral infection is caused by or associated with a coronavirus that causes severe acute respiratory syndrome (SARS), such as a SARS virus or MERS virus, e.g. SARS-CoV, SARS-CoV-2, or MERS-CoV. Preferably the viral infection is caused by or associated with SARS-CoV-2.

[00131] Pathogenic respiratory viral infections can cause disease and symptoms associated with the viral infection. In certain embodiments the formulation is for use in the prevention or treatment of a disease or condition associated with a respiratory viral infection in the subject. Thus is may be that the formulation is for use in the treatment or prevention of a respiratory syndrome caused by or associated with a respiratory viral infection in the subject. For example the treatment or prevention of severe acute respiratory syndrome (SARS) in the subject. Thus it may be that formulation is for use in the prevention or treatment of severe acute respiratory syndrome caused by SARS-CoV, SARS-CoV-2, or MERS-CoV, preferably the treatment or prevention of severe acute respiratory syndrome caused by SARS-CoV-2 in the subject.

[00132] In a preferred embodiment the formulation is for use in the treatment of COVID-19 in the subject.

[00133] COVID-19 can be diagnosed by any method known to the skilled person. Samples (e.g., sputum, mucus, sera, nasal aspirate, throat swab, broncho-alveolar lavage or other types of body fluids) from subjects can be obtained and tested for the presence of SARS- CoV-2. Exemplary methods for diagnosing an infection with SARS-Cov-2 include, but are not limited to, detection of a nucleotide sequence of a SARS-CoV-2 virus (e.g. using PCR), detection of a SARS-Cov-2-associated coronavirus antigen, and antibodies or fragments thereof that immunospecifically bind to a SARS-CoV-2-associated coronavirus antigen.

[00134] Subjects with respiratory viral infections can develop serious conditions associated with the viral infection. Intranasal treatment of the subject with a respiratory viral infection using the formulation may prevent or treat a condition selected from: sepsis, pneumonia or organ failure associated with a respiratory viral infection. In some embodiments the formulation is for use in the intranasal treatment or prevention of sepsis caused by or associated with the respiratory viral infection in the subject. In some embodiments the formulation composition is for use in the intranasal treatment or prevention of pneumonia caused by or associated with the respiratory viral infection. The pneumonia may be viral pneumonia or bacterial pneumonia (e.g. bacterial pneumonia caused by or associated with secondary bacterial infection in the lung of a subject). Thus it may be that the formulation is for use in the intranasal treatment or prevention of viral pneumonia in the subject.

[00135] In certain embodiments the respiratory viral infection is caused by or associated with influenza virus. The influenza virus may be type A; type B, type C or type D. Type A and B viruses cause seasonal epidemics in humans, while type A viruses have caused several pandemics. Type C viruses generally cause mild illness and are not generally associated with epidemics. Type D viruses primarily affect cattle. Type A viruses can be divided into subtypes based on their surface proteins hemagglutinin (H) and neuraminidase (N). There are 18 different hemagglutinin proteins (designated H1 to H18) and 11 different neuraminidase proteins (designated N1 to N 11). This gives 198 potential influenza A type combinations, although only 131 subtypes have been detected to date. The viral infection may be caused by or associated with a Type A influenza virus selected from H1 N1 , H1N2, H2N2, H3N2, H5N1, H7N7, H9N2, H7N2, H7N3, H10N7, H7N9 and H6N1. Type B viruses are not classified into subtypes, but can be categorised into lineages. Type B viruses may belong to either the B/Yamagata or B/Victoria lineage.

[00136] In certain embodiments the formulation is for use in the intranasal treatment or prevention of a symptom of a respiratory viral infection (e.g. SARS-CoV-2) in the subject selected from fever (e.g. a fever above 38 °C), cough, sore throat, shortness of breath, respiratory distress, and pneumonia. Suitably the formulation is used to intranasally treat severe acute respiratory syndrome (SARS).

[00137] Niclosamide has anti inflammatory properties. Accordingly intranasal administration of the formulation to the subject may be beneficial in reducing, ameliorating or treating pulmonary inflammation associated with respiratory viral infections, because niclosamide has both antiviral and anti inflammatory properties.

[00138] In certain embodiments the formulation is for use in the intranasal treatment or prevention of pulmonary inflammation caused by or associated with respiratory viral infection in the subject. For example the intranasally administered formulation may reduce or eliminate inflammation of tissues in the respiratory tract.

[00139] In certain embodiments the formulation is for use in preventing or repressing pro- inflammatory cytokines caused by or associated with the respiratory viral infection in the subject. Thus it may be that the intranasally administered formulation reduces one or more of CRP leukocytes, IL1B, IL-6, IL-10, IL-2, IFNy, IP10, MCP1 , GCSF, IP10, MCP1, MIP1A, and/or TNFa, particularly reducing serum CRP. In some embodiments the intranasal administration of the formulation reduces levels of IL-6 in the subject with a respiratory viral infection.

[00140] Respiratory viral infections ( including, but not limited to SARS CoV-2) can induce cytokine release syndrome (CRS) (also known as a cytokine storm syndrome (CSS)). CRS is a systemic inflammatory response triggered by the viral infection and results in the sudden release of large numbers of pro-inflammatory cytokines which can damage organs and in particular may lead to respiratory failure. Recent publications suggest that cytokine storm is observed in some patients with severe forms of COVID-19 (Zhang et al, International Journal of Antimicrobial Agents https://doi.Org/10.1016/j.ijantimicag.2020.105954 , available online 29 March 2020). In some embodiments the formulation is for use intranasally in the prevention, repression or treatment of cytokine release syndrome in the subject with a respiratory viral infection (e.g. a subject infected with SARS-CoV2, SARS or MERS).

[00141] In certain embodiments the formulation has an antiviral effect on the respiratory virus, for example by preventing or inhibiting viral replication. Without wishing to be bound by theory, it is believed that the formulation can act as an antiviral by to inhibiting or preventing viral replication in at least the respiratory tract of the subject. Accordingly, in some embodiments the formulation is for intranasal use in preventing or inhibiting viral replication in the subject with a respiratory viral infection. In some embodiments the formulation may reduce or eliminate the viral load in the subject.

[00142] In some embodiments of the invention the aerosol or solution is used as an antiviral and as an anti-inflammatory and/or as an anti-bacterial. Thus, in some embodiments the solution is used as at least a dual therapy or triple therapy. Thus, in some embodiments the solution can be used to target respiratory viral infection and inflammation and/or bacterial infection for the treatment of an RTI, for example in a coronaviral infection such as SARS. In some embodiments the solution is used as an anti-viral, as an anti-inflammatory and as an anti-bacterial for the treatment of an RTI, for example in a coronaviral infection such as SARS.

[00143] In some embodiments formulation is used to intranasally treat a respiratory viral infection in the subject as an antiviral (e.g. to prevent viral replication) and to further provide one or more of the following additional therapeutic effects: anti-bacterial; anti-inflammatory; reduction or prevention of bronchoconstriction/to cause bronchodilation; and/or reduction of mucus production and/or secretion.

[00144] The subject infected with a respiratory viral infection may be asymptomatic at the early stages of a viral infection. Treatment of asymptomatic subjects may prevent the viral infection becoming symptomatic and/or developing diseases or medical conditions associated with the respiratory viral infection. Accordingly also provided is the formulation for use in the treatment of an asymptomatic subject infected with a respiratory virus (e.g. a SARS virus such as SARS-CoV-2).

[00145] Niclosamide may provide a particularly effective treatment against viral infections such as SARS-CoV-2. Evidence has suggested that niclosamide possesses broad spectrum antiviral properties, including against SARS-CoV-2 (Xu et al., J ACS Infect Dis 2020; Wu etal., Antimicrob Agents Chemother 2004:48:2693-6). It has been suggested that the mode of action of niclosamide may include inhibition of autophagy, viral replication and receptor-mediated endocytosis of SARS-CoV2 (Pindiprolu etal., Medical Hypotheses 140 (2020) 109765).

[00146] Some respiratory viral infections become contagious before symptoms emerge in a subject infected with the virus, for example as is the case with SARS-Cov-2. This can result in high rates of transmission of the virus in a population, because the infected host does not know that they are contagious and inadvertently spreads the virus through social contact etc. Transmission of a virus by asymptomatic subjects can be particularly dangerous after an initial infection is contained in a population, because asymptomatic, but contagious, subjects can trigger a resurgence of infections and a “second wave” of viral infection. Using the formulation to intranasally treat an asymptomatic subject with a respiratory viral infection may reduce the time that a subject is contagious by, for example reducing or eliminating the virus from the subject and/or to speed up seroconversion in the subject (i.e. the production of antibodies to the virus by the subject’s immune system). Intranasal treatment using the formulation may reduce the viral shedding from the subject, thereby making the subject less contagious. Viral shedding refers to the number of virus leaving the body of the subject in for example mucous droplets resulting from coughing or sneezing, or present in other excreta.

[00147] Accordingly, in some embodiments the formulation is for use in the treatment of a respiratory viral infection in an asymptomatic subject, wherein the treatment reduces or eliminates the viral load in the subject. In some embodiments the formulation is for use in the intranasal treatment of a respiratory viral infection in an asymptomatic subject, wherein the treatment accelerates seroconversion in the subject. In some embodiments the formulation is for use in the intranasal treatment of a respiratory viral infection in an asymptomatic subject, wherein the treatment reduces inter-subject transmission of the virus. In some embodiments the formulation is for use in the intranasal treatment of a respiratory viral infection in an asymptomatic subject, wherein the treatment reduces viral shedding.

The viral infection in a preferred embodiment SARS-CoV-2. [00148] In some embodiments, the formulation is for use in the intranasal treatment of SARS-Co /2 in an asymptomatic subject. The subject may have tested positive for SARS- CoV-2 (e.g. via a PCR test). The treatment may be started within 0-5 days, or within 1-3 days, of the positive test result (day 0 being the day the test result is received by the subject). Intranasally administering the formulation to an asymptomatic subject may prevent or reduce the risk of the subject developing symptoms of mild, moderate or severe COVID- 19, particularly symptoms of moderate to severe COVID-19. Intranasal treatment of an asymptomatic subject may also reduce the number of members of the subject’s household who become infected with SARS-CoV-2. In some embodiments, intranasal administration of the formulation to an asymptomatic subject reduces the time-weighted change (reduction) from baseline through day 10. In other words, the formulation may reduce the risk of, or prevent, the progression of the disease. In an asymptomatic subject, “baseline” refers to the subject having no symptoms.

[00149] The detection of a respiratory viral infection in an asymptomatic subject may be achieved using known testing methods, for example tests which detect the presence of the virus in saliva samples such as real-time reverse transcription polymerase chain reaction (rRT-PCR) or PCR methods. In some embodiments the formulation is for use in the intranasal treatment or prophylaxis of a subject who has received a positive diagnosis of a respiratory viral infection, such as COVID-19 (SARS-CoV-2). The subject may be suffering from mild, moderate or severe COVID-19, or they may be asymptomatic. Prophylactic intranasal treatment of subjects who have not received a positive test for the presence of SARS-CoV-2 infection, or who have not been tested, is also envisaged.

[00150] Symptoms of COVID-19 are non-specific and the disease presentation can range from no symptoms (asymptomatic) to severe pneumonia and death. The clinical progression of COVID-19 shows a biphasic pattern. The first phase is characterized by fever, cough, fatigue and other systemic symptoms like dizziness and headache, shortness of breath, rhinorrhoea, sore throat, diarrhoea and inappetence. Fever is seen in most of the patients with an estimated median duration of 10 days (95 confidential intervals after onset of symptoms (Chen et al. Clinical progression of patients with COVID-19 in Shanghai, China. J Infect. 2020;80(5):e1-e6.).

[00151] As the disease progresses into the second phase, symptoms begin to relieve in most of the patients and radiological improvement occurs in parallel. In line with body temperature reduction, patients also become PCR negative with their upper respiratory tract samples (mean time to viral clearance is around 11 days). There is however a small sub- group of patients (~5%) which present with respiratory failure, septic shock, and multiorgan dysfunction, resulting in higher fatality rates. Persistent fever, lung damage and diseases progression can be partially explained by uncontrolled viral replication. The persistence of COVID-19 can also induce excessive but aberrant non-effective response which is associated with cytokine storm.

[00152] Patients with “mild” COVID-19, as used herein, are subjects with a score of 2, 3 or 4 on the modified WHO scale described below. Subjects may be ambulatory or hospitalized. They show symptoms of COVID-19 that could include fever, cough, sore throat, malaise, headache, shortness of breath, muscle pain, loss of taste and/or smell, ocular symptoms (e.g. one or more of conjunctival hyperemia, chemosis, epiphora, or increased secretions) and/or gastrointestinal symptoms (e.g. diarrhoea) of variable intensity and they can either have no or mild signs of viral pneumonia. They may display a limitation of daily activities. They do not need oxygen treatment.

[00153] Patients with “moderate” COVID-19, as used herein, are subjects with a score of 5 on the modified WHO scale described below. Subjects are hospitalized with COVID-19 needing treatment with oxygen by mask or nasal prongs. They show symptoms that could include fever, cough, sore throat, malaise, headache, muscle pain and/or gastrointestinal symptoms of variable intensity. They have a moderate pneumonia.

[00154] Patients with “severe” COVID-19, as used herein, are subjects with a score of 6, 7 or 8 on the modified WHO scale described below. These subjects require intensive care and/or mechanical ventilation or extra-corporeal membrane oxygenation. Such patients may display hypoxemia, extrapulmonary hyper-inflammation, severe pneumonia, vasoplegia, respiratory failure, cardiopulmonary collapse and/or systemic organ involvement. Markers of systemic inflammation (e.g. IL-2, IL-6, IL-7, granulocyte colony-stimulating factor, macrophage inflammatory protein 1-a, tumor necrosis factor-a, C-reactive protein, ferritin, and/or D-dimer) may be elevated.

[00155] In any of the embodiments described herein, the subject may be hospitalized.

By targeting patients at a stage where viral replication is high but has not yet led to severe tissue damage, the treatment may reduce duration of symptoms, minimize contagiousness, and prevent progression of severity and poor outcome. Accordingly, in some embodiments the formulation is for use in the intranasal treatment of a respiratory viral infection in a subject suffering from mild or moderate COVID-19. In some embodiments, the subject suffering from mild or moderate COVID-19 is hospitalized. In some embodiments, the subject is suffering from moderate COVID-19 and is hospitalized. In some embodiments, the subject is suffering from mild COVID-19 and the formulation is administered intranasally. In some embodiments, the subject is suffering from moderate COVID-19 and the formulation is administered intranasally. In some embodiments, the subject is suffering from mild or moderate COVID-19 and is hospitalized, wherein the formulation is administered intranasally. It may be that intranasal administration of the formulation is for preventing, or reducing the likelihood of, progression of the disease, e.g. from mild to moderate or from moderate to severe COVID-19.

[00156] It may be that intranasal administration of the formulation increases the time to incidence of any one or more of the following: Death; invasive mechanical ventilation;

ECMO; Cardiovascular organ support (e.g. balloon pump or inotropes/vasopressors); or renal failure (cockcroft-gault estimated creatine clearance <15 ml/min, hemofiltration or dialysis).

[00157] In some embodiments, intranasal administration of the formulation to the subject has one or more of the following effects:

- A reduction in the level of biomarkers thought to be associated with progression of COVID- 19, such as ferritin, CRP, D-Dimer, neutrophil to lymphocyte ratio, LDH;

- A change in the clinical status of the subject as assessed on a 7-point ordinal scale (Table 13) compared to baseline;

- An improvement in SPO2/F1O2;

- A reduction in the time to Sp0₂ >94% on room air;

- A reduction in the time to a first negative SARS-CoV-2 PCR result;

- A reduction in the duration of oxygen therapy;

- A reduction in the duration of hospitalization;

- A reduction in the time to clinical improvement (for example a greater than 2 point improvement from day 1 on the 7-point ordinal scale).

[00158] In some embodiments, the subject is identified as being at risk of disease progression. For example, the subject may be identified as being at risk of progressing from mild to moderate, or from moderate to severe COVID-19. In some embodiments, the subject may be identified as being at risk of an increase in the subject’s score on the modified WHO scale, as described below. A skilled doctor or nurse will be capable of identifying at-risk subjects. For example, a subject who is at risk of disease progression may be identified based on one or more factors, which may include clinical parameters (such as the subject’s respiratory status, blood oxygen saturation, temperature, severity of flu-like symptoms, chest X-ray or other scans, inflammatory biomarker levels, viral load and the presence of underlying conditions) and, optionally, non-clinical parameters (such as subject’s age and gender).

[00159] The treatment may reduce or eliminate the viral load in the subject (e.g. the viral load in sputum or blood), for example, it may be that the treatment reduces the viral load in the nasal cavity. It may be that the treatment reduces the viral load in the lungs of a subject. In some embodiments, the treatment reduces the time taken to cure the disease, relative to a patient not treated with the formulation. The treatment may avoid the need for hospitalization in patients with mild COVID-19, or reduce hospitalization time for patients with moderate COVID-19. The treatment may prevent the progression of the disease. For example, the treatment may prevent progression from mild to moderate, or from moderate to severe COVID-19. The treatment may prevent an increase in a subject’s score on a modified WHO scale as described below. The treatment may reduce or eliminate the need for oxygen therapy. The treatment may increase blood oxygen levels. The treatment may prevent or reduce the risk of respiratory failure. The treatment may reduce the time for viral clearance from a subject. The treatment may reduce or eliminate viral colonization. For example the treatment may reduce or eliminate viral colonization in the nasal cavity. It may be that treatment reduces or eliminates viral colonization in the lungs.

[00160] In some embodiments, the formulation is for use in the intranasal treatment of a viral infection in subject suffering from severe COVID-19.

[00161] The treatment may reduce the time the patient spends in intensive care, relative to a patient not treated with the formulation. In some embodiments, the treatment improves the efficacy of a co-administered drug, such as an anti-inflammatory agent. The treatment may reduce the severity of symptoms, the recovery time, and/or the long term effects of the disease.

[00162] In some embodiments, the formulation is for use in the intranasal treatment of a respiratory viral infection (e.g. COVID-19), wherein said treatment includes one or more of the following: a reduction in the severity of flu-like signs and symptoms (e.g. temperature); an improvement in the respiratory status of the subject as assessed by oximetry (blood oxygen saturation); an improvement in the NEWS2 score; an improvement in the score on the modified WHO ordinal scale, as described herein; reduction or elimination of pulmonary inflammation and/or edema; an improvement in respiratory function; a reduction in shortness of breath; a reduction in the time to viral clearance; a reduction in the time to discharge from hospital; reduced viral load; a reduction in inflammatory serum markers (e.g. CRP, procalcitonin). In some embodiments, treatment results in subjects having an improvement in the score on the modified WHO ordinal scale by 1 to 6 grades, 2 to 5 grades, or 3 to 4 grades. In some embodiments, treatment results in subjects having an improvement in the NEWS2 score by from 1 to 6 points, from 2 to 5 points, or from 3 to 4 points.

[00163] Also provided is a prophylactic treatment wherein the formulation intranasally administered to a subject to prevent or reduce the risk of contracting a respiratory viral infection. In certain embodiments the formulation is for use in reducing the risk of, or preventing, a subject contracting a respiratory viral infection. Such prophylactic treatments may be particularly beneficial to subjects that may be exposed to high levels of a virus, for example doctors, nurses and healthcare workers that are caring for people with viral infections.

[00164] In some embodiments, the formulation is prophylactically administered intranasally. In some embodiments, the formulation is prophylactically administered intranasally to a subject who has been, or is suspected as having been, in close proximity with a person who is diagnosed as being infected with SARS-CoV-2. For example, family, co-workers and/or other close contacts of an infected individual, who are identified as having being at risk of exposure to the virus, may be administered the formulation as a prophylactic treatment. The close contacts of the infected individual may be identified via a tracking and tracing program, such as a government-operated program. Prophylactic treatment of subjects after suspected exposure to an infected person may be beneficial in preventing further spread of the virus. In some embodiments, the subject starts the prophylactic treatment no more than 7 days, no more than 6 days, no more than 5 days, no more than 4 days, no more than 3 days, no more than 2 days or no more than 24 hours after the exposure, or suspected exposure, to the infected individual. The close contacts may be subjects who are identified as having been in close proximity to the infected individual and include, for example, subjects who share a home, office, school or mode of transport with the infected individual, those who have taken part in a sport or other social activity with the infected individual, and those who may have come into close proximity with the infected individual in a public space such as a restaurant, bar, cafe, transport terminal, library, hospital or other medical facility, or shop. Preferably, prophylactic treatments may be administered intranasally. It is advantageous that prophylactic treatment of the invention is administered to the subjects described herein, for example in the case of an epidemic or in the case of incidence of SARS-CoV-2 infection in a close contact of the subjects, such as a member of the household, medical personal, etc. [00165] In some embodiments, the formulation is prophylactically administered intranasally to a subject who has had recent exposure to SARS-CoV2. In these embodiments, “recent exposure to SARS-CoV2” is defined as exposure of the subject to a household member within the 5 days prior to the household member (the “index case”) developing symptoms of SARS-CoV2 and/or testing positive for COVID-19 (day 0 being the first day of symptoms in the index case or the day of a positive PCR result if the index case is asymptomatic).

[00166] In some embodiments, the prophylactic intranasal administration provides at least a 30-50% reduction in the incidence of symptomatic or asymptomatic SARS-CoV-2 infection, for example following recent exposure of the subject to SARS-CoV-2. It may be that the prophylactic intranasal administration reduces the likelihood of the subject developing nasopharyngeal SARS-CoV-2, for example after being in close proximity to an infected individual, e.g. following recent exposure of the subject to SARS-CoV-2 as defined above. It may be that the prophylactic intranasal administration reduces the duration of SARS-Cov-2 excretion. The incidence of symptomatic/asymptomatic SARS-CoV-2, the development of nasopharyngeal SARS-CoV-2 and/or the duration of SARS-Cov-2 excretion may be determined after a predetermined treatment period, e.g. 3, 4, 5, 6, 7, 8, 9 or 10 days of treatment, optionally after a further predetermined period without treatment, e.g. 3, 4, 5, 6 or 7 days of no treatment. For example, the subject may be evaluated at day 12, including 7 days of prophylactic treatment and 5 days of no treatment (day 0 being the first day of symptoms in the index case or the day of a positive PCR result if the index case is asymptomatic).

[00167] The treatments and prophylactic treatments described herein may also be particularly beneficial to subjects who are at particularly high risk from COVID-19. These subjects include: those with an existing disease or condition in addition to being a subject undergoing dialysis, a kidney transplant recipient or a subject with vasculitis, an auto immune kidney disease or glomerulonephritis. Such additional conditions could be diabetes (Type I or Type II diabetes mellitus, in particular poorly controlled diabetes), cancer, heart disease (such as heart failure, coronary artery disease and cardiomyopathy), hypertension (in particular poorly controlled hypertension), cerebrovascular disease, SCID, sickle cell disease (including sickle cell anaemia), thalassemia, pulmonary fibrosis, interstitial lung disease, chronic lung disease such as COPD, asthma (particularly moderate to severe asthma) and cystic fibrosis, emphysema, bronchitis, chronic kidney disease, chronic liver disease, hepatitis, autoimmune disease (including systemic lupus erythematosus (SLE)), a genetic immune disease, Anti-GBM, rheumatoid arthritis, psoriatic arthritis, connective tissue disease, spondyloarthritis, polymyalgia rheumatica, inflammatory bowel disease (including Crohn’s disease and ulcerative colitis, coeliac disease, aplastic anaemia, Addison’s disease, Graves’ disease, Hashimoto’s thyroiditis, myasthenia gravis, pernicious anaemia and Sjogren’s syndrome), a condition affecting the brain or nerves (such as Parkinson’s disease, motor neurone disease, multiple sclerosis, dementia, mental illness or cerebral palsy, and subjects who have suffered from a stroke), a muscle wasting condition, or a severe or profound learning disability. Subjects at high or moderate risk from COVID-19 also include subjects who have a weakened immune system, for example due to a disease, condition or treatment. These subjects include: subjects who have had a body tissue transplant, such as an organ transplant (including liver, lung and/or heart transplant recipients); subjects who have had an organ (e.g. their spleen) removed; subjects receiving (or who have received) chemotherapy, immunotherapy, antibody therapy or radiotherapy; subjects receiving (or who have received) cancer treatment; subjects receiving (or who have received) protein kinase inhibitors or PARP inhibitors; subjects who have had a blood, bone marrow or stem cell transplant (e.g. in the last 6-12 months); subjects who are immunocompromised, including subjects taking immunosuppressants (e.g. ciclosporin, tacrolimus, azathioprine, mycophenolate mofetil or mycophenolic acid, belatacept, methotrexate, tocilizumab, abatacept, leflunomide, prednisolone, anti-TNF (e.g. infliximab, adalimumab, etanercept), cyclophosphamide, rituximab or alemtuzumab), or steroids), subjects with HIV or AIDS; subjects who are very obese (with a BMI of at least 30, at least 40 or above); and subjects who are pregnant. Also included are subjects who smoke; care home residents; staff working in care homes for adults over 50, 60, 65, 70, 75 or 80 years of age; frontline health and/or social care workers; and subjects who are over 50, 60 or 70 years of age, in particular subjects over 75, 80, 85 or 90 years of age.

[00168] Thus, in some embodiments the formulation is for intranasal use in reducing the risk of, or preventing, a subject contracting a respiratory viral infection (e.g. COVID-19), wherein the subject is at a high or moderate risk from COVID-19, for example wherein the subject is selected from the groups defined above. In some embodiments, the formulation is for use intranasally in prophylaxis of non-infected subjects who are at high or moderate risk from COVID-19, such as a subject selected from the groups defined above. It may be that the prophylaxis is for reducing the risk of the subject contracting symptomatic or non- symptomatic COVID-19 infection. The prophylaxis may be for reducing the risk of mortality, and/or the severity of symptoms (should the subject contract COVID-19). It may be that the prophylaxis is for reducing the risk of the subject contracting moderate or severe COVID-19. The risk may be reduced by from 10 to 100%, from 20 to 90%, from 30 to 80%, from 40 to 70% or from 50 to 60%. [00169] In some embodiments, the prophylaxis reduces the risk of the subject contracting a secondary infection (e.g. a secondary bacterial infection), wherein the subject is at a high or moderate risk from COVID-19, for example wherein the subject is selected from the groups defined above. It may be that the prophylaxis reduces the risk of mortality, or the severity of, the secondary infection. The risk of contracting a secondary infection, or mortality resulting from a secondary infection, may be reduced by from 10 to 100%, from 20 to 90%, from 30 to 80%, from 40 to 70% or from 50 to 60%.

[00170] In certain embodiments the formulation is for use in intranasally treating a respiratory viral infection in a subject (e.g. COVID-19), wherein the subject is selected from the groups defined above.

[00171] In some embodiments, said treatment comprises intranasally administering the formulation to the subject with a respiratory viral infection in combination with a further therapeutic or prophylactic agent. The further therapeutic or prophylactic agent may be an anti-viral agent (e.g. Remdesivir), an anti-inflammatory agent (e.g. a steroid, such as dexamethasone), an immunosuppressive agent, a neutralizing antibody or an antithrombotic agent. The further therapeutic or prophylactic agent may be administered using any route (e.g. orally, or per-orally). A Combination therapy may be beneficial for subjects with a severe respiratory viral infection (e.g. severe COVID-19).

Dosage and dosage regimens

[00172] The dosage and dosing regimen of the formulation will depend upon a number of factors that may readily be determined by a physician, for example the severity of the respiratory viral infection, the responsiveness to initial treatment and the particular respiratory viral infection being treated. Examples of suitable doses, dosing volumes and frequencies are set out in the brief summary of the disclosure above.

[00173] The total daily dose of the niclosamide administered to the subject may comprise one or more unit doses. The total daily dose may be from 5 to 1000 mg, from 6 to 800 mg, from 8 to 700 mg, from 10 to 500 mg, from 15 to 400 mg, from 30 to 300 mg, from 50 to 250 mg, from 100 to 200 mg or from 120 to 250 mg of the niclosamide, or pharmaceutically acceptable salt thereof.

[00174] In some embodiments the total daily dose is from 1 to 50 mg, from 1.5 to 40 mg, from 2 to 30 mg, from 2.5 to 20 mg, from 3 to 15 mg, from 3.5 to 12 mg, from 4 to 10 mg, from 4.5 to 9 mg, from 5 to 8.5 mg, from 5.5 to 8 mg, from 6 to 7.5 mg or from 6.5 to 7 mg of the niclosamide or pharmaceutically acceptable salt thereof (niclosamide or niclosamide ethanolamine). In some embodiments the total daily dose is 5.6 mg niclosamide ethanolamine, corresponding to 4.7 mg niclosamide free acid.

[00175] In embodiments wherein the formulation is in the form of a solution, a volume of from 50 to 250 pi, or from 100 to 200 mI (e.g. 130-150 mI) per nostril may be administered intranasally, and a volume of from 1 to 10 ml, from 2 to 8 ml or from 3 to 7 ml (e.g. 4-6 ml) may be administered intraorally (e.g. via a nebulizer). In some embodiments, a volume of 140 mI per nostril is administered intranasally (e.g. via an intranasal delivery device. The solution may be dosed, for example twice daily. In some embodiments a volume of 140 mI per nostril is administered intranasally in a dose of 1 4mg of niclosamide ethanolamine salt per nostril twice daily, approximately 12 hours apart. Thus giving a total daily dose 5.6mg niclosamide ethanolamine salt (4.7mg free niclosamide acid).

[00176] The formulation may be administered once per day, or multiple times (e.g. 2, 3 or 4 times) per day. In some embodiments the formulation is administered twice daily.

[00177] The total daily volume administered to the subject may be from 200 mI to 20 ml, from 300 mI to 19 ml, from 500 mI to 18 ml, from 1 ml to 17 ml, from 2 ml to 16 ml, from 3 to 15 ml, from 4 to 14 ml, from 5 ml to 12 ml or from 8 ml to 10 ml of the formulation when in the form of a solution. In some embodiments, the formulation is a solution containing from 0.1 to 5%, from 0.5 to 5%, from 1 to 4%, from 1.5 to 3% (e.g. from about 1 to 2%) of the niclosamide, or a pharmaceutically acceptable salt thereof.

[00178] The formulation may be administered to the subject over a number of consecutive days or weeks. For example, the formulation may be administered one or more times daily over a period of from 3 days to 6 weeks, from 7 days to 4 weeks from 10 days to 3 weeks or from 14 to 18 days. In some embodiments, the formulation is administered over a period of from 1 week to 1 year, from 2 weeks to 9 months, from 4 weeks to 6 months, from 6 weeks to 4 months, or from 2 to 3 months. For example, the treatment may be administered for up to 6 to 9 months. In some embodiments, the formulation is administered to the subject twice daily for up to 10, 14 or 28 days. It will be appreciated that the dosing period will be determined by the type and severity of the disease being treated, or whether the formulation is being administered prophylactically. For example, for the treatment of chronic respiratory viral infections (e.g. chronic moderate or severe cases of COVID-19), the treatment duration may be longer (e.g. at least 4 weeks, at least 6 weeks, at least 8 weeks or at least 12 weeks). It may be that treatment is continued until the subject has recovered from the respiratory viral infection. [00179] In some embodiments, the subject is intranasally administered 100-200 mI (e.g. 120- ISO mI or 130-160 mI) per nostril of a 1% solution of niclosamide ethanolamine, twice per day. In a preferred embodiment, the subject is intranasally administered 140 mI per nostril of a 1% solution of niclosamide ethanolamine, twice per day.

[00180] It will be appreciated that the dose of the formulation and/or the dosage regime may be selected by the skilled person depending on a number of factors such as, but not limited to, the severity of the disease, the age of the subject and/or the presence of any underlying conditions.

[00181] In some embodiments, the formulation is administered to a subject for the treatment or prophylaxis of COVID-19. In some embodiments wherein the subject is suffering from mild COVID-19, the subject is asymptomatic, or the subject is being treated prophylactically (e.g. a subject in a high-risk group, or a close contact of an infected individual), the formulation may be administered one or more times daily for a period of no more than 21 days, no more than 18 days, no more than 16 days, no more than 14 days, no more than 12 days or no more than 10 days. In some embodiments wherein the subject is suffering from moderate or severe COVID-19, the formulation may be administered one or more times daily for a period of at least 7 days, at least 10 days, at least 14 days, at least 21 days or at least 28 days.

[00182] As will be appreciated the doses and dosage regimens set out in this section may be used with any of the formulations disclosed herein. In a preferred embodiment the formulation used in any of the doses and dosage regimens described herein and in this “dosage and dosage regimens” is a liquid formulation comprising: about 1 % niclosamide ethanolamine; about 15% cyclodextrin, preferably a b-cyclodextrin, more preferably HR-b-CD; about 2% PVP (e.g. PVP 30); the balance being water, wherein the percentages are by weight based on the weight of the liquid formulation; and optionally wherein the formulation has a pH of from 7.0 to 8.5, for example from 7.5 to 7.8, or from 7.6 to 8.0, preferably about 7.8.

Combination Therapies

[00183] The formulation may be used alone to provide a therapeutic effect. The formulation may also be used in combination with one or more additional therapeutic agents. [00184] In some embodiments the additional therapeutic agent is selected from one or more of:

• an antiviral agent (e.g. remdesivir, a HIV protease inhibitor (e.g. lopinavir or ritonavir), or a 3CL protease inhibitor (e.g. PF-07304814);

• a vaccine (e.g. a COVID-19 vaccine), examples of vaccines include weakened or inactivated viral vaccines, replicating or non-replicating viral vector vaccines, nucleic acid vaccines (RNA or DNA vaccines), protein subunit vaccines or virus-like particle vaccines;

• bronchodilators, e.g. short acting beta agonists (e.g. albuterol, epinephrine or levalbuterol), or long acting beta agonists (e.g. formoterol, salmeterol or vilanterol);

• anticholinergics (e.g. ipratropium);

• leukotriene modifiers (e.g. montelukast, zafirlukast, or zileuton);

• long-acting bronchodilators (e.g. tiotropium);

• anti-inflammatory agents (e.g. steroids, which may be intravenous, oral or inhaled steroids (e.g. dexamethasone, budesonide); non-steroidal anti-inflammatory agents (e.g. ibuprofen, naproxen, ketoprofen or carprofen, a COX-2 inhibitor such as celecoxib), an anti-inflammatory antibody (e.g. benralizumab, dupilumab, mepolizumab, omalizumab, reslizumab);

• an antibacterial agent, for example a Gram-positive or Gram negative antibiotic;

• an anti-viral antibody (e.g antibodies that act against the spike proteins of a corona virus such as SARS-CoV-2 (e.g. LY-CoV555, LY-C0VOI6, AZD7442, REGN10933,or REGN10987); and antibodies from subjects that have previously been infected with a virus (e.g. convalescent plasma therapies); or a combination of any two or more thereof.

[00185] Such combination treatment may be achieved byway of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the formulation of this invention within a therapeutically effective dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

[00186] Herein, where the term “combination” is used it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention “combination” refers to simultaneous administration. In another aspect of the invention “combination” refers to separate administration. In a further aspect of the invention “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

[00187] In some embodiments in which a combination treatment is used, the amount of the formulation and the amount of the other pharmaceutically active agent(s) are, when combined, therapeutically effective to treat a targeted disorder in the patient. In this context, the combined amounts are “therapeutically effective amount” if they are, when combined, sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder; cure the disorder; reverse, completely stop, or slow the progress of the disorder; or reduce the risk of the disorder getting worse. Typically, such amounts may be determined by one skilled in the art by, for example, starting with the dosage range described in this specification for the niclosamide, or pharmaceutically acceptable salt thereof present in the formulation and an approved or otherwise published dosage range(s) of the other pharmaceutically active agent(s).

Preparation of formulations

[00188] The formulation may be prepared by the following method:

- adding cyclodextrin and/or niclosamide, or a pharmaceutically acceptable salt thereof, to a solvent to form a suspension;

- heating the suspension for a period of time sufficient for the cyclodextrin and/or the niclosamide, or a pharmaceutically acceptable salt thereof, to dissolve in the solvent, thereby forming a solution;

- cooling the solution.

[00189] In some embodiments, the method comprises adding both the cyclodextrin and the niclosamide, or a pharmaceutically acceptable salt thereof, to the solvent prior to heating.

[00190] Further methods for preparing the formulation are set out in the Examples

EXAMPLES

The invention is further illustrated by the following examples.

Abbreviations

CD Cyclodextrin

DMSO Dimethylsulfoxide NEN Niclosamide ethanolamine

OXY Oxyclozanide

PVP Polyvinyl pyrrolidone Example 1 : Aqueous Formulation Comprising Niclosamide Ethanolamine

The formulation shown in Table 1 was prepared as described below:

Table 1 :

Niclosamide ethanolamine (100 mg), PVP K30 (200 mg) and hydroxypropyl beta- cyclodextrin (1500 mg) were weighed into a 20 ml. glass vial. To this powder mixture was added milliQ water (8.5 mL), 2 drops 5M NaOH, and 100 mI_ DMSO. The pH of the mixture was at least 8

The vial was placed in an ultrasonic bath at 65 °C and mixed according to the following schedule: vortex for 1 to 10 minutes; ultrasonication at 65 °C; vortex for 1 to 5 minutes; ultrasonication at 65 °C; and vortex 1 min; to provide a clear red composition without any visible particles.

2 drops 5M HCI were added to the composition followed by vortexing for 1 minute. The resulting formulation was cooled to room temperature and the pH adjusted to 7.80 ± 0.1 using 1 M NaOH/HCI to give the title formulation. The Osmolarity of the title composition was 180 mOsm/kg.

Formulations B to E shown in Table 2 were prepared using an analogous method

Table 2:

Example 2: Storage Stability of Aqueous Niclosamide Ethanolamine Formulations

A sample of Formulation A described in Example 1 was stored under refrigerated conditions at 5°C in darkness. Another sample was stored at room temperature exposed to ambient light. After 74 days storage both samples were analysed for degradation of the niclosamide using the following HPLC-UV method:

Column: Kinetex C18 100 A LC column (4.6 ^c 100 mm, 5 pm) from Phenomenex Mobile phase A: 0.1 M acetate buffer adjusted to pH 4.0 Mobile phase B: methanol Injection volume: 5 pL Flow rate: 1.0 mL/min

Detection wavelength: 310 nm Measurement time: 10 min

Gradient conditions: Time %A %B

0.00 70 30

5.00 20 80

7.50 20 80

7.60 70 30

Results

The sample stored under refrigerated conditions in darkness showed 0.6 % degradation of niclosamide. The sample stored at room temperature showed 0.7 % degradation of niclosamide.

Example 3: Antibacterial Effects of Niclosamide Against Bacteria Associated with

Pulmonary Bacterial Infections such as Pneumonia

Microorganisms

Bacterial strains were chosen for their relevance regarding lung infections, such as pneumonia: Staphylococcus aureus , methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pyogenes. S. aureus and S. pyogenes strains are as defined in WO 2016/038035.

Strains were conserved in Luria Bertani (LB) Broth (S. aureus) or Brain Heart Infusion (BHI) (S. pyogenes) supplemented with glycerol 15% (v/v) at -80 °C, and reactivated by isolation on LB (S. aureus) or BHI (S. pyogenes) agar plates. Strains were cultivated in Mueller Hinton (MH) Broth-cation adjusted (S. aureus) or BHI (S. pyogenes). All strains were cultivated aerobically (microaerobically for S. pyogenes strains) at 37 °C.

The following tests were performed to assess the antibacterial activity of niclosamide in vitro :

Minimum inhibitory concentration (MIC) assay

The MIC was determined according to the method described in WO 2016/038035.

Results Table 3: MIC values in pg/mL for niclosamide using the above described assay.

The MIC of niclosamide was < 0.5 mg/mL against all targeted strains.

The results in Table 3 show that niclosamide is effective against a range of bacteria, including bacteria commonly associated with lung infections. Accordingly, the inhalable compositions comprising niclosamide may be effective in the treatment or prevention of bacterial lung infections, including secondary bacterial lung infections associated with cystic fibrosis, COPD and respiratory viral infections.

Example 4: Batch manufacturing of niclosamide ethanolamine solution The formulation shown in Table 4 was prepared as described below:

Table 4

as required to provide a pH of about 7.8 The nebuliser solution 1% is an isotonic and euhydric aqueous formulation. The solution was filled into 10 ml. clear type I moulded glass vials, each vial containing 7 mL of the solution. The nebuliser solution 1% contains 10 mg/ml_ niclosamide ethanolamine, equivalent to 8.4 mg/ml_ of niclosamide free base. The batch formula for 10 kg nebuliser solution 1% is shown in Table 5:

Table 5

*as required to provide a final pH of about 7.8

The bulk solution was prepared in a class C environment according to the following protocol:

1. A tank was charged with hot water (e.g. 65-90 °C) for injection (80% of the total quantity) and stirring was started;

2. The tank was charged with cyclodextrin and NaOH and the mixture stirred until the solid components were completely dissolved to provide a solution of about pH 12;

3. Solid niclosamide ethanolamine was added to the tank and stirring was continued until the niclosamide ethanolamine was completely dissolved to give a solution of approximately pH 8-9;

4. 75% of the total of 2N HCI was added;

5. PVP was added and stirring continued until the PVP was completely dissolved;

6. The solution was cooled to about room temperature;

7. The pH of the solution was adjusted to 7.8 by addition of the remaining 2N HCI, and the pH was recorded;

8. Water for injection was added to the final weight;

9. The solution was discharged into 10 mL glass vials (7 ml_ solution per vial);

10. The vials were closed with a rubber stopper and sealed with an aluminium cap.

The results of analysis of batches manufactured according to the above protocol are shown below in Table 6:

Table 6

Example 5: Physical stability of niclosamide ethanolamine aqueous solution

The stability of different formulations comprising niclosamide ethanolamine, cyclodextrin and polymer was evaluated. Materials used

Methods

Sample preparation Table 7 shows the compositions of 18 different formulations which were prepared. The cyclodextrin, polymer and NEN were weighed into a 20 ml. glass vial. To this, 100 pl_ of 5 M NaOH was added along with water for injection (WFI) to yield 10 g of formulation, and the mixture was vortexed for 1 min. The suspension was then ultrasonicated at 70 °C for 5 min and vortexed for 1 min. This procedure was repeated two times or until a clear solution was achieved. The resulting solution was then cooled to room temperature and the pH is adjusted to 7.8-8.0 using 1 M or 5 M HCI. After pH adjustment, the formulation was vortexed for 1 min.

Stability study

After preparation, the formulations were divided into three 4 mL black capped brown glass vials and stored at 5 °C (dark), 25 °C (light) and 40 °C (dark) at ambient humidity. The samples were evaluated visually for precipitation after 1, 2, 7, 14 and 28 days of storage.

Table 7: Composition of the different formulations. The remaining fraction constitutes WFI. Formulation NEN Kleptose Captisol PVP 17 PVP 30 PVP/VA HPMCAS

1 2% 10% 2%

2 2% 10% 2%

3 2% 10% 2%

4 2% 10% 2%

5 2% 15% 2%

6 2% 15% 2%

7 2% 15% 2%

8 2% 15% 2%

9 1% 10% 2%

10 1% 15% 2% 11 2% 10% 2% 12 2% 10% 2%

13 2% 10% 2%

14 2% 10% 2%

15 2% 15% 2%

16 2% 15% 2%

17 2% 15% 2%

18 2% 15% 2%

Results

Formulations 12, 13, 14, 16, 17 and 18 never formed a clear solution upon preparation. Formulations 4 and 15 precipitated upon the final pH adjustment. The remaining samples were stored at 5 °C (dark), 25 °C (light) and 40 °C (dark).

Precipitation observed after storage at 5 °C (dark)

Day 1: None

Day 2: Formulations 1 , 7, 11 Day 7: Formulations 1 , 7, 11 Day 14: Formulations 1, 3, 7, 11 Day 28: Formulations 1, 3, 7, 11

Precipitation observed after storage at 25 °C (light) Day 1: Formulations 1, 7, 11 Day 2: Formulations 1 , 3, 7, 11 Day 7: Formulations 1 , 3, 7, 11 Day 14: Formulations 1, 2, 3, 6, 7, 11 Day 28: Formulations 1, 2, 3, 6, 7, 11

Precipitation observed after storage at 40 °C (dark)

Day 1: Formulations 1 , 3, 7, 11 Day 2: Formulations 1 , 2, 3, 6, 7, 11 Day 7: Formulations 1, 2, 3, 5, 6, 7, 11 Day 14: Formulations 1, 2, 3, 5, 6, 7, 8, 11 Day 28: Formulations 1, 2, 3, 5, 6, 7, 8, 9, 11

Conclusion

The formulations containing Kleptose were significantly more stable than formulations containing Captisol. Furthermore, the formulations containing 15% Kleptose (Formulations 5- 8) were generally more stable than the formulations containing 10% Kleptose (Formulations 1-4) and the formulations containing 1% NEN and PVP K30 (Formulations 9 and 10) were generally more stable than the formulations containing 2% NEN and PVP K30 (Formulations 2 and 6). Storage at lower temperatures increased the physical stability. Formulation 10 (1% NEN, 2% PVP K30 and 15% Kleptose) did not show any sign of precipitation after 12 weeks storage at 5 °C and 25 °C. Furthermore, it precipitated later than Formulation 5 after storage at 40 °C and therefore, Formulation 10 displayed the best physical stability of the 18 different formulations tested in this study.

Example 6: Test of nasal atomization device with niclosamide solution

Tests were carried out to determine the suitability of a nasal applicator device for the administration of formulation 10 of Example 5. The device tested was the MAD Nasal™ Intranasal Mucosal Atomization Device (catalogue no. MAD130), with a 1.0 mL syringe.

Methods

- Differential weighting with a 4 digit balance.

- SprayTec from Malvern at 15 L/min (LALLS, Low-Angle Laser Light Scattering).

Test descriptions and results

Initial Test: The formulation was taken into the syringe by inserting the blue plastic needle into the vial with active formulation. The blue needle was then removed and the MAD Nasal device was attached. Not much hand force was needed. Spray with water: About 0.5 mL was sucked up into a fresh syringe. The blue needle was then removed and a MAD Nasal device attached. Two alternative spray direction was then applied, MAD Nasal device down and MAD Nasal device up. Table 8. Remaining amount of formulation in the syringe after use

Remaining amount of water (mL)

MAD Nasal device down 0.08

MAD Nasal device up 0.19

LALLS testing: Droplet size distribution was assessed twice with similar results, as shown in Table 9. Table 9. D10, D50 and D90 for two LALLS tests (in pm).

D10 D50 D90

Test 1 33 65 159

Test 2 30 62 209

Dose variability testing: Six new (directly taken from the pouch) MAD Nasal devices were tested with the formulation using the following procedure:

1) The syringe was removed from the plastic pouch and weighed. 2) The syringe was filled with formulation up to 0.35 mL on the syringe and weighed.

3) The needle was exchanged with the MAD Nasal device and weighed.

4) The syringe was emptied with the tip down and weighed.

The Results are shown in Table 10 below. Table 10: Results of differential weighing for six devices.

Conclusions The MAD Nasal device was found to work well with the formulation. Filling the device to 0.35 ml. resulted in a dose of approximately 0.15 mL with some variability due to manual handling.

Example 7: Non-clinical studies

Study A: Dose Range Finding and 2 Week GLP Inhalation Toxicity Study in the Rat

The objectives of this study were to determine the potential toxicity of the formulation shown in Table 4 of Example 4 (1% niclosamide ethanolamine, 2% PVP K30 and 15% Kleptose HPB) , when given by inhalation administration to rats at escalating dose level to determine a maximum tolerated dose (MTD Phase) followed by a 2 week repeat dose phase (Fixed Dose Phase) and to evaluate the potential reversibility of any findings. In addition, the toxicokinetic characteristics of Formulation A were determined.

The pivotal 2-week safety study in rats was assessed using daily dose levels of 15 (5-fold higher [systemic mg/kg] and 18-fold higher [local mg/g] compared to a human 30 mg, qd dose) and 50 mg/kg (15-fold higher [systemic mg/kg] and 52-fold higher [local mg/g] compared to a human 30 mg, qd dose) (10 rats/sex/group for main study evaluation); both vehicle and air control groups were also included. This pivotal phase was preceded by a range finding phase which selected a high dose level of 50 mg/kg for use in the pivotal 2- week phase. Microscopic evaluation of the nasal cavity in rats after 2 weeks of daily dosing revealed a non-adverse minimal hypertrophy of goblet (mucin-secreting) cells in the nasal septum/nasopharynx at 15 and 50 mg/kg which was not dose related; these changes were not observed in the vehicle or air control groups and were considered an adaptive change to repeated administration of niclosamide ethanolamine. In the lungs, minimal to mild increase in alveolar macrophages were observed after 2 weeks of dosing in the vehicle and 15 and 50 mg/kg dose groups; these changes were not considered adverse but instead an adaptive to response to clearance of the vehicle. No other noteworthy histopathological findings have been reported to date.

Study B: Dose Range Finding and 2 Week GLP Inhalation Toxicity Study in the Beagle Dog

The objectives of this study were to determine the potential toxicity of the formulation shown in Table 4 of Example 4, when given by inhalation administration to dogs at escalating dose level to determine a maximum tolerated dose (MTD Phase) followed by a 2 week repeat dose phase (Fixed Dose Phase) and to evaluate the potential reversibility of any findings. In addition, the toxicokinetic characteristics of the formulation were determined.

The pivotal 2-week safety study in dogs was assessed using daily dose levels of 2.5 (2-fold [systemic mg/kg] and 4-fold higher [local mg/g] to a human 30 mg, qd dose) and 4.37/4.14 mg/kg (3-fold higher [systemic mg/kg] and 6-fold higher [local mg/g] compared to a human 30 mg, qd dose) (3/sex/group for main study evaluation); both vehicle and air control groups were also included. After 2 weeks of daily dosing, microscopic evaluation in male and female dogs administered vehicle or 2.5 mg/kg and in females dosed at 4.14 mg/kg revealed no changes to the nasal cavity and only minimal changes in the lungs including minimal increased alveolar macrophages and mixed/mononuclear cell infiltration, minimal bronchial exudate, and mild neutrophilic infiltration or mild increased cellularity in tracheobronchial lymph node secondary to the minimal lung findings. The histological changes seen after 2 weeks of dosing were minor and not considered adverse.

Study C: Pulmonary pharmacokinetics of nebulized niclosamide in sheep following pulmonary administration (non-GLP)

The objectives of this study were to determine the pharmacokinetic profile of the formulation shown in Table 4 of Example 4, when given by pulmonary administration to sheep at escalating dose levels similar to the clinical escalation scheme coupled with a safety assessment using lung function tests.

The PK analysis in the sheep following treatment demonstrated substantial exposure of niclosamide in the epithelial lining fluid (ELF). Peak concentrations exceed 100-fold of the IC90 value of niclosamide against SARS-CoV-2. In spite of substantial clearance from the ELF, niclosamide concentrations above the IC90 are maintained for the 8-hour sampling period following a single administration the formulation (Figure 1A). These data support the twice daily administration of the formulation.

Additionally, the ELF concentrations of niclosamide in this study greatly exceed the published plasma pharmacokinetics published from studies using oral niclosamide and provide the pharmacological rationale for using formulations according to the invention for treatment of COVID-19 compared to oral dosage forms of niclosamide. As viral elimination is most likely driven by pulmonary rather than systemic exposure, the efficacy margin achieved with Formulation A following pulmonary administration is much greater (efficacy margin of mean Cmax in ELF to IC90 is >100 fold) in the relevant region of viral replication than the one with the oral route (efficacy margin mean systemic exposure of human oral dose to IC90 exists only for 2g/day dose, which is 8-fold), although definite lung levels after oral administration of niclosamide remain unknown (Figure 1B).

Niclosamide systemic exposure after administration was in the range of values reported in humans following oral exposure, with Cmax of 577 ng/mL (mean) [range: 217-803 ng/mL] Additionally, the treatment was found to be well tolerated in the sheep as determined by lung function analysis pre and post dosing.

Example 8: Phase I Trial of Inhaled Niclosamide

A randomized, placebo-controlled, double-blind, multiple dosing Phase 1 trial was conducted to assess the safety of the formulation shown in Table 4 of Example 4 (or an equivalent formulation comprising 0.1% w/w niclosamide, the balance being water) in healthy volunteers.

Methods

Trial design and oversight

This was a single centre, interventional, double-blinded (open label for the first sentinel subject within each cohort), placebo-controlled, Phase 1 study to assess the safety and explore PK parameters of niclosamide ethanolamine in healthy volunteers (HV). The study consisted of five cohorts, which started one after the other, each after consultation of the Safety Monitoring Committee (SMC). Each cohort started only if the previously collected data did not give raise to safety concerns. 44 eligible HVs were enrolled in five sequential cohorts for dose finding, each cohort were screened generally followed by extended respiratory work-out one or two days before dosing. If all inclusion and no exclusion criteria were met, dosing was fulfilled followed by 24 hours monitoring. After 48 hours, all participants had the same extensive respiratory work-out as prior to the study inclusion. 34 of these 44 healthy controls receive the investigational product (IP), and 10 the placebo. The study was partly conducted in an open-label design (first subject in cohort 1-4 as sentinel subject), and partly double blinded (subsequent subjects in cohorts 1-4 and all subjects in cohort 5). The doses of the different cohorts are displayed in Table 11.

Table 11 : Summary of cohorts with its dose and duration of treatment Cohort Dose

1 9 healthy volunteers, 7 received a single dose of formulation (4 mL, 0.1%, equalling

3.4 mg niclosamide) and nasal spray (2 x 150 pL, 0.1 %, i.e. once per nostril, totalling 0.25 mg niclosamide) and 2 received placebo

2 9 healthy volunteers, 7 received a single dose of formulation (1 mL, 1 %, equalling 8.4 mg niclosamide) and nasal spray (2 x 150 pL, 1%, totalling 0.25 mg niclosamide) and 2 received placebo.

3 9 healthy volunteers, 7 received a single dose of formulation (3 mL, 1%, equalling 25.2 mg niclosamide) and nasal spray (2 x 150 pL, 1%, totalling 0.25 mg niclosamide) and 2 received placebo.

4 9 healthy volunteers, 7 received a single dose of formulation (6 mL, 1%, equalling

50.4 mg niclosamide) and nasal spray (2 x 150 pL, 1%, totalling 0.25 mg niclosamide) and 2 received placebo.

5 8 healthy volunteers, 6 received five doses of formulation (6 mL, 1%, equalling 50.4 mg niclosamide per dosing and 252 mg in total) and nasal spray (2 x 150 pL, 1%, totalling 2.5 mg niclosamide per dosing and 12.6 mg in total) dosed BID for 2.5 days and 2 received placebo.

For cohorts 1-4, one subject was dosed with the IP the first day (Monday) and followed for 24 hours while admitted at the clinic to assess safety of the new dose. Safety visit with extended lung function measurements were performed the following Wednesday to Friday at CFAS. For cohort 5, patients received a total of 5 administrations and stayed at the trial site for 3 days (Monday or Tuesday onto Thursday or Friday), including overnight. In cohort 5, as the dose was the same as in cohort 4, all patients were blinded and randomized. Safety visit with extended lung function measurements were performed the following Thursday to Saturday at CFAS.

Throughout the study, both IP were administered by qualified study staff. Each treatment was assigned to a specific subject by randomization number. Screening and enrolment was done sequentially for one cohort after the other. A randomization number was assigned in ascending order to each eligible subject at Day 0 according to the randomization list by cohort. The first number of the cohorts 1 , 2, 3 and 4 was always active (open label) and the remaining consisted of 6 active and 2 placebos (n=9). For cohort 5, the numbers consisted of 6 active and 2 placebos (n=8).

Eligibility

Subjects who signed Informed Consent Form (ICF), were male or nonpregnant and nonlactating female who was abstinent or agreed to use effective contraceptive methods throughout the course of the study, females who had a negative urine beta-human chorionic gonadotropin hormone (hCG) pregnancy test prior to and did not need to agree to use contraception, showed an electrocardiogram (ECG) without clinically significant abnormalities (including QTcF < 450 ms), were > 18 and < 65 years at the time of signing ICF, were normally active and in good health by medical history with no current chronic diseases and normal physical examination, had minimum 80% of predicted lung function, including expiratory volume (FEV1) after (32-agonist, static volume (TLC), diffusion capacity (DCO), and normal cardiopulmonary exercise testing (CPET) with pulse oximetry as well as ECG with a fitness score of > 20 ml_0₂/kg*min for females and > 25 ml_0₂/kg*min and no clinical important arrythmia or desaturation during exercise and furthermore, showed a chest X-ray without clinically significant abnormalities were eligible to participate in this study. Subject that had clinically significant allergies, current acute or chronic condition, renal impairment, underlying condition that may interfere with inhalation of IP, and consumed alcohol in the 24 hours prior dosing were excluded.

Safety assessment and outcome measures

Safety was assessed through the following parameters: adverse events (AEs) reporting, general safety assessments, general physical examination, vital signs, clinical laboratory analysis, including urinalysis, haematology, and serum chemistry, ECGs, vital capacity, TLC, DCO, FEV1, reversibility, fraction of expiratory nitric oxide (FeNO) tests, resting pulse oximetry and CPET with ECG and pulse oximetry.

The primary endpoint was defined as the AE frequency in each cohort and treatment group and the change from baseline for all safety variables measured and frequency of out of range values. Furthermore, the pharmacokinetics following administration was evaluated by determining the maximum concentration of active drug molecules in blood (Cmax), time to reach maximum level (Tmax), area under the curve of drug level in blood versus time (AUC) and the half-life (T½).

Primary endpoints

• AE frequency in each cohort and treatment group

• Change from baseline for all safety variables measured and frequency of out of range values

• In addition to AEs/SAEs collection throughout the study duration, general safety will be assessed via clinical examination, vital sign assessments, ECGs, and laboratory analysis (serum chemistry, hematology, and urinalysis). • Pulmonary function monitored by measurement of vital capacity, expiratory volume (Forced Respiratory Volume in one second, FEV1), static volume (Total Lung Capacity, TLC), diffusion capacity (DCO), exhaled nitric oxide (FeNO) and resting pulse oximetry. Secondary endpoints - PK

• Maximum concentration of active drug molecules in blood (Cmax)

• Time to reach maximum level (T_max)

• Area Under the Curve of drug level in blood versus time (AUC)

• Half life Statistical Analysis

The sample size was considered sufficient to meet the study objectives and to assess treatment safety but was not based on statistical power considerations. Two sets of populations for analysis were distinguished, the Safety Set and the PK Set. The Safety Analysis Set includes data from all enrolled subjects receiving any amount of IP. Descriptive statistics are reported for continuous variables and metric values, including the number of subjects, mean (m), standard deviation (SD), median, minimum (Min), and maximum (Max). Categorical variables are reported as frequencies and percentages. For metric values, absolute change of since baseline are reported, except for FEV1 percentage change is shown. Significance of differences was tested in an exploratory fashion. No imputation for missing data was made. Data from patients receiving placebo were combined across cohorts. For all analyses, the statistical software Stata® (version 16) was used in the most recent sub-version available at data base lock.

The PK Analysis Set included data from subjects who were treated and have no missing data affecting the PK assessment. Subjects with at least one quantifiable drug concentration were included in the PK analysis. No imputation for missing data was made. All pharmacokinetic parameters were calculated using non-com partmental analysis (NCA) with a validated installation of the software Phoenix® WinNonlin® version 8.1.

Results

Trial population Forty-four subjects were randomized of which 34 were assigned to treatment and 10 to placebo.

Safety Outcomes

No serious AE nor early discontinuation was reported in this study. In total, 32 subjects experienced one or more AEs during the study. The majority of the AEs belonged to the “Respiratory, thoracic, and mediastinal disorders” category with “Upper respiratory tract irritation” being the most frequent AE descriptor (45 events in 26 subjects, 59%) and corresponding to throat irritation during and after nebulization.. Furthermore, the nasal applications did not result in any finding with regards to local tolerability. For the nebulization procedure, there was a dose-dependent difference in terms of tolerability.

However, all AEs reported were mild and disappeared spontaneously and completely without treatment in one to two hours. For most subjects, symptoms were more pronounced during the first 5-10 minutes of the inhalation procedure. Of note, in the multiple administration group, most subjects reported that symptoms decreased over time with repeated dosing. During administration of the drug, some subjects showed an asymptomatic, but significant decrease in FEV1 (> 200ml_ and >12%), which was reversible with a beta2 agonist, whereas none of the subjects experienced decrease in FVC, nor in DCO.

Asymptomatic airway obstruction (decline in FEV1) was shown in 4 subjects, 3 out of 4 occurring in the highest dose (6 mL) group. These events were all responsive to inhaled b2- mimetic treatment.

In cohort 5, the mean (SD) oxygen uptake was unchanged 3401 (551) prior to drug administration and 3359 (516) (NS), and the mean workload was similar at the two measurements 309 (56) versus 300 (54), NS). Likewise, the FEV1 post beta2-agonist was 116 (16) pre-drug values, and post drug administration 111 (17) (NS), and FVC 117 (14) and 114 (13), respectively (NS) and TLC 104 (11) and 104 (10), respectively (NS). DCO was found to have a significant decrease 102 (10) versus 90 (6), p=0.01, however none showed a clinically significant change of more than 20%. Post drug safety lung function measurements showed asymptomatic decrease in post beta2-agonist FEV1 measurement 1 participants (from 124%pred to 108 %pred), two developed significant reversibility (18% and 12%), and 4 had signs of increased airway inflammation (identified as a change in fractional nitric oxide concentration in exhaled breath [FENO]) (Change of 11 ppb, 37 ppb, 37 ppb, 28 ppb) of whom one had elevated FeNO prior to drug administration, all in Cohort 5. None showed clinically significant change in TLC, or VCLmax in cohort 1 to 5. One showed a decrease in DCO in cohort 3 (15%) and 3 in cohort 5 (19%, 18%, 16%), however KCO was in all cases unchanged within the clinical acceptable limit.

All but one of the AEs related to abnormal test values were reported with the highest dose in either cohort 4 or cohort 5 and all these events were reported in the active groups and considered by the investigator as being possibly, probably or definitely related to the test product or procedure.

Pharmacokinetics

Pharmacokinetic analyses demonstrated dose-proportional characteristics for niclosamide ethanolamine (Figure 2). The maximum plasma concentration (Cmax) and Area under the curve (AUCo-e) levels following a single dose application were 238.9 ng/mL (mean) and 509.0 hr^*ng/ml_ (mean). Following repeated dosing in Cohort 5, C_max and AUCo-s levels of 337.3 ng/mL and 401.2 hr*ng/mL were reported, indicating no accumulation of niclosamide ethanolamine after repeated dosing.

Raw data indicated peak concentrations in blood of 337 ng/mL (mean) [range: 29-506 ng/mL] after repeated inhalation doses. The half-life was shown to be 2 hours (mean) in cohort 4 and 2.7 hours (mean) in cohort 5. This is in the range of systemic exposure reported after oral dosing of niclosamide (see Figure 3). The systemic PK data from humans (including dose response) is in close agreement with the data from the sheep PK study (see Figure 4).

As a preliminary conclusion, the formulation appears to provide systemic exposure within the range observed with the approved 2g oral dosage form of niclosamide (Yomessan). Additionally, given the route of administration and the sheep ELF PK data, the concentration in the lungs is substantially higher than oral niclosamide and accordingly the formulation would represent a preferred treatment of COVID19 compared to oral dosage forms of niclosamide.

Example 9: Double-blind placebo controlled trial of prophylactic niclosamide against

SARS-CoV2 infection in vulnerable patients with kidney or autoimmune diseases

A double-blind placebo controlled trial of prophylactic niclosamide against SARS-CoV2 infection in vulnerable patients with kidney or autoimmune diseases, including patients in receipt of dialysis, kidney transplant recipients, individuals with vasculitis, systemic lupus erythematosus and glomerular disease receiving immunosuppression, using intranasal administration of the formulation shown in Table 4 of Example 4 will be carried out. This clinical trial aims to enrol patients at particularly high risk of COVID-19 and its complications, seeking to test whether intranasal niclosamide might prevent the disease from occurring. Participants will be randomised 1:1 to niclosamide or matching placebo.

The trial will administer 1% niclosamide ethanolamine solution via a nasal spray pump twice daily (140mI_ of a 1% niclosamide ethanolamine solution, equivalent to 1.4mg of niclosamide ethanolamine salt pernostril twice daily; total daily dose 5.6mg niclosamide ethanolamine salt (4.7mg free niclosamide acid).

Trial Design

A randomised, double blind, placebo controlled event driven trial evaluating the use of nasal niclosamide as a prophylactic agent against COVID-19 infection.

Trial Population

Approximately 1500 participants will be enrolled from three vulnerable patient populations: dialysis patients, kidney transplant recipients and those with vasculitis or other auto-immune kidney disease such as systemic lupus erythematosus (SLE) or glomerulonephritis (GN).

The provisional distribution between trial populations will be 1:1:1 (dialysis:transplant:vasculitis/SLE/GN). No capping for a specific subgroup will be implemented but it is expected to have a minimum of 150 patients in each subgroup arm, or 300 patients per intervention plus placebo, approximately. However, the proportion of the total trial population represented by each subgroup may be adjusted depending on the event rate of the primary outcome measure within each patient group. The subgroup-specific event rate will be monitored monthly.

Inclusion Criteria

To be included in the trial the participant must:

• Be aged 18 years or older

• Have given written informed consent

• Be a member of one of the following vulnerable patients populations

Dialysis- including in centre haemodialysis, home haemodialysis and peritoneal dialysis o Kidney transplant receiving at least one of the immunosuppressive medications listed in Table 12 o Vasculitis (according to Chapel Hill Consensus Conference 2012 definitions) or systemic lupus erythematosus (SLE) receiving atleast one of the immunosuppressive medications listed in Table 12 o Glomerulonephritis* receiving at least one of the immunosuppressive medications listed in Table 12.

* Glomerulonephritis includes prior histological confirmation of any of the following conditions - minimal change nephropathy, focal segmental glomerulosclerosis (FSGS), IgA nephropathy, primary membranous nephropathy, membranoproliferative glomerulonephritis or lupus nephritis.

Table 12

Exclusion criteria

• Inability to provide informed consent or to comply with trial procedures

• COVID-19 at time of enrolment - either positive SARS CoV-2 swab (PCR) or symptoms highly suggestive of COVID-19 infection.

• Known chronic liver disease or hepatic dysfunction as evidenced by ALT or AST > 3x upper limit of the normal range.

• Allergy to niclosamide or history of significant adverse reaction to niclosamide or related compounds, or to any of the excipients used.

• Significant structural nasal disease in the opinion of the investigator.

• Pregnant, trying to conceive, unwilling to use contraception or breastfeeding

• Participation in another interventional prophylactic or vaccine trial* against COVID- 19.

*Patients wi l l remain eligible for enrolment if they have received SARS-COV-2 vaccination as part of routine care.

Trial Treatments

Niclosamide Nasal Spray 1% and matching Nasal Spray Placebo will be provided in 10 mL amber glass vials with nasal spray pumps, containing 8.5 mL of the respective solution, delivering 140 pL per spray shot.

Niclosamide Dose

140 pL of a 1% niclosamide ethanolamine solution in each nostril twice daily, equivalent to 1.4 mg of niclosamide ethanolamine salt per nostril twice daily, approximately 12 hours apart. Total daily dose 5.6 mg niclosamide ethanolamine salt (4.7 mg free niclosamide acid). The doses will be administered using a single metered dose nasal pump spray per nostril twice daily.

Pharmacokinetic Assessment

Population Pharmacokinetic (PK) assessment will be conducted in the first 30 participants receiving niclosamide for safety purposes, to exclude the unlikely possibility of accumulation of niclosamide during the course of the trial in patients receiving dialysis only. Given that participants and investigators will be blinded to treatment allocation, PK samples will maintain blinding by including the first 70 dialysis patients in the PK sampling cohort. Including 70 participants is necessary to exclude the scenario where a chance imbalance in treatment allocation early in the study results in fewer than 30 participants allocated to niclosamide. These participants will be identified as the ‘PK Cohort’. The PK Cohort will have a blood sample taken at the start of dialysis, before taking the IMP. PK Cohort participants receiving dialysis in the afternoon or evening may take the morning dose of IMP, but should omit the evening dose until the PK sample has been obtained. The procedure for obtaining PK samples is described in the trial procedures manual.

PK samples will be obtained 7 (±3) days after the date of first IMP dose (or coincident with the 3rd dialysis session post-dating randomisation), 14 (±3) days and 21 (±3) days after date of first dose.

Duration of Study

The trial will be an event driven trial. The median anticipated treatment period is 6 months with a maximum treatment period of 9 months. Last follow-up visit will be scheduled 4-6 weeks after last dose.

Primary Objective

The primary aim of the trial is to determine if nasal niclosamide reduces the risk of confirmed symptomatic COVID-19 infection in vulnerable renal and immunosuppressed patients participating in the study. Secondary Objectives

1) Determine if nasal niclosamide increases the time to confirmed SARS-Cov-2 infection from the date of randomisation including incidental asymptomatic cases in the vulnerable populations taking part in the study.

2) Determine the safety of nasal niclosamide in this patient population 3) Determine if nasal niclosamide reduces mortality and severity of COVID-19 infection in the vulnerable populations taking part in the study.

Exploratory Objectives

1) Determine if nasal niclosamide reduces the occurrence of other influenza infections in the vulnerable populations taking part in the study. 2) Determine if nasal niclosamide increases the proportion of individuals with antibodies to SARS-Cov-2 at the end of the trial in the vulnerable populations taking part in the study.

Trial Outcomes

The primary outcome for PROTECT is confirmed symptomatic COVID-19 infection during treatment.

The primary outcome event is defined as the presence of both

PCR confirmed SARS-CoV2 and

One or more symptoms in keeping with COVID-19, including:

Respiratory (Cough +/- sputum and shortness of breath)

Constitutional (Pyrexia/chills, myalgia/arthralgia, fatigue, rash, headache, confusion) Gastrointestinal (nausea/vomiting, diarrhoea, abdominal pain, loss of appetite)

The date (time) of the primary outcome event is defined as the date of the confirmed COVID- 19 test.

Secondary Outcomes Secondary outcomes include a. Time to confirmed SARS-Cov-2 infection from the date of randomisation including asymptomatic cases. b. Safety and All-cause mortality. c. Severity of COVID-19 disease (assessed by PI 28 days after date of positive test) assessed by: i. Adapted WHO ordinal scale (defined as the worst category 28 days from date of positive test or until date of discharge from hospital, whichever occurred later)

1. Healthy carriers - confirmed SARS-CoV2 infection, no symptoms

2. Very mild symptoms, no limitations

3. Mild, limitations on activities

4. Mild, hospitalised, no oxygen requirement

5. Moderate, hospitalised, oxygen via mask or nasal cannulae

6. Severe, non-invasive ventilation or high flow oxygen

7. Very severe, intubation and mechanical ventilation 8. Critical, ventilation and additional organ support (RRT/ECMO)

9. Death ii. Length of inpatient stay iii. Common COVID-19 complications (including Acute Respiratory Distress Syndrome (ARDS), viral pneumonitis, myocarditis/myocardial injury, acute kidney injury)

Exploratory Outcomes

Exploratory outcomes will include

1. Occurrence of antibodies to SARS-CoV-2 at the end of the trial

2. Occurrence of other influenza infection (swab confirmed) 3. Occurrence of other respiratory viral infections (aside from COVID-19 and influenza)

4. Staphlococcus aureus infections (dialysis population only)

Efficacy Analysis

The Intent to Treat (ITT) population is defined as all participants randomised in the trial, regardless of whether they actually received trial treatment. The treatment group will be analysed as randomised.

The primary outcome measure, symptomatic Covid-19 infection, will be compared between each prophylactic treatment and the randomised placebo groups in the ITT population using a Cox proportional hazards model, adjusting with fixed effects for Age

Sex

Ethnicity

Patient population (dialysis, vasculitis/glomerulonephritis, transplant)

Known high-risk pre-existing conditions (e.g. cardiovascular disease, hypertension, diabetes mellitus), vs not.

Detectable anti SARS-COV-2 antibodies at baseline

Receipt of Covid-19 vaccination (a time-dependent covariate)

Randomisation option (one prophylactic treatment vs two prophylactic treatments) The hazard ratio will be determined and statistical significance will be declared using a 2- sided alpha-level of 0.045. A 95% confidence internal for the hazard ratio from the Cox model will be provided.

Participants who did not develop symptomatic COVID-19, withdrew from the study, are lost to follow-up or died prior to developing symptomatic COVID-19 will be censored at the date of last treatment administered. Asymptomatic PCR confirmed COVID-19 participants will be followed up for a maximum of 4 weeks (this is consistent with the maximum of 4 week treatment after positive COVID-19). If any protocol specified symptoms have occurred, the date of the positive COVID-19 test is the date of primary endpoint event; otherwise, the participant will be censored at the date of last follow up, or last treatment administered, if self-administering IMP.

For the secondary outcome measure of time-to-PCR-confirmed SARS-Cov-2 infection in the ITT population, the analysis will use a Cox proportional hazards model as described for the primary outcome measure. The median, 25th and 75th percentile and 95% Cis for time to PCR confirmed SARS-CoV-2 infection will be provided. The severity scale of COVID-19 disease will be compared using a proportional odds model for all COVID-19 infected participants. Length of inpatient stay will be compared using Fine and Gray approach with discharge alive as event of interest and hospital death as competing event for all hospitalised participants.

Common COVID-19 complications for all COVID-19 infected participants and occurrence of influenza infection in the ITT population will be analysed using the standard chi-square test. The comparisons on the secondary outcome measures will be compared according to a prespecified hierarchal order.

Method of analysis at the end of trial

If efficacy is observed for more than one prophylactic intervention, comparisons between different prophylactic treatments will be performed at the end of trial in an exploratory manner.

Sample Size

It is planned to randomise (1:1 ratio) a total of 1500 participants approximately during a period of 3-6 months.

Claims

1. A formulation comprising niclosamide, or a pharmaceutically acceptable salt thereof, and a cyclodextrin, for use in the treatment or prevention of a respiratory viral infection in a subject in need thereof; wherein the formulation is administered to the subject intranasally; and the subject is selected from (i) a subject undergoing dialysis, (ii) a kidney transplant recipient and (iii) a subject with vasculitis, systemic lupus erythematosus (SLE), an auto-immune kidney disease or glomerulonephritis.

2. A method for treating or preventing a respiratory viral infection in a subject in need thereof, the method comprising the intranasal administration of a formulation comprising niclosamide, or a pharmaceutically acceptable salt thereof, and a cyclodextrin; and wherein the subject is selected from (i) a subject undergoing dialysis, (ii) a kidney transplant recipient and (iii) a subject with vasculitis, systemic lupus erythematosus (SLE), an auto-immune kidney disease or glomerulonephritis.

3. The formulation for use or method according to claim 1 or claim 2, wherein the subject is a subject undergoing dialysis.

4. The formulation for use or method according to claim 3, wherein the subject is a subject undergoing dialysis selected from: centre haemodialysis, home haemodialysis and peritoneal dialysis.

5. The formulation for use or method according to claim 1 or claim 2, wherein the subject has glomerulonephritis.

6. The formulation for use or method according to claim 3, wherein the subject has a condition selected from: minimal change nephropathy, focal segmental glomerulosclerosis (FSGS), IgA nephropathy, primary membranous nephropathy, membranoproliferative glomerulonephritis and lupus nephritis.

7. The formulation for use or method according to any one of claims 1 to 6, wherein the subject is treated concurrently with an immunosuppressant therapy, optionally wherein the immunosuppressant therapy is selected from one or more of: a calcineurin inhibitor, a purine synthesis inhibitor, a inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitor, a T cell co-stimulation blocker, a folic acid derivative, an IL-6 receptor inhibitor, a T-cell activation inhibitor, a dihydroorotate dehydrogenase (DHODH) inhibitor, a corticosteroid, an anti-TNF therapy, a B-lymphocyte stimulator (BLyS) inhibitor, an alkylating agent, an anti-CD20 therapy, and an anti-CD52 therapy.

8. The formulation for use or method according to claim 7, wherein the immunosuppressant therapy is selected from one or more of: ciclosporin, tacrolimus, azathioprine, mycophenolate mofetil or mycophenolic acid, belatacept, methotrexate, tocilizumab, abatacept, leflunomide, prednisolone, sirolimus, an anti-TNF therapy (e.g. infliximab, adalimumab, or etanercept), belimumab, cyclophosphamide, rituximab and alemtuzumab.

9. The formulation for use or method according to any preceding claim, wherein the viral infection is caused by or associated with a virus selected from respiratory syncytial virus, influenza virus, parainfluenza virus, human metapneumovirus, severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), a human rhinovirus (HRVs) and human adenovirus (HAdV).

10. The formulation for use or method according to any preceding claim, wherein the viral infection is caused by or is associated with a Pneumoviridae virus, for example a Human respiratory syncytial virus (HRSV) (e.g. HRSV-A2, HRSV-B1 or HRSV-S2).

11. The formulation for use or method according to any one of claims 1 to 8, wherein the viral infection is caused by or associated with a Coronaviridae virus.

12. The formulation for use or method according to claim 11, wherein the virus is selected from Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus.

13. The formulation for use or method according to claim 12, wherein the virus is a Betacoronavirus.

14. The formulation for use or method according to claim 13, wherein the virus is selected from severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), HCOV-229E, HCoV-NL63, HCoV-OC43 and HKU1.

15. The formulation for use or method according to any one of claims 1 to 8, wherein the viral infection is caused by or associated with SARS-CoV-2.

16. The formulation for use or method according to claim 15, wherein the viral infection is COVID-19.

17. The formulation for use or method according to claim 16, wherein the viral infection is moderate or mild COVID-19.

18. The formulation for use or method according to claim 16, wherein the viral infection is moderate or mild COVID-19 and the subject is hospitalized.

19. The formulation for use or method according to claim 16, wherein the viral infection is severe COVID-19.

20. The formulation for use or method according to claim 16, wherein the viral infection is asymptomatic COVID-19.

21. The formulation for use or method according to any one of claims 16 to 20, wherein the treatment or the method prevents, or reduces the likelihood of, progression of the disease, e.g. from mild to moderate or from moderate to severe COVID-19.

22. The formulation for use or method according to any one of claims 16 to 20, wherein the treatment or the method is for:

- reducing the risk of the subject contracting symptomatic or non-symptomatic COVID-19 infection; - reducing the risk of mortality from COVID-19;

- reducing the severity of symptoms of COVID-19;

- reducing the risk of the subject contracting moderate or severe COVID-19; or

- reducing the duration of hospitalisation.

23. The formulation for use or method according to any one of claims 1 to 8, wherein the viral infection is caused by or associated with influenza virus.

24. The formulation for use or method according to any of the preceding claims, wherein the subject has an existing condition or disease selected from: heart disease, chronic lung disease (such as COPD, asthma or cystic fibrosis), kidney disease, diabetes, hypertension, cancer, a genetic immune disease.

25. The formulation for use or method according to any of the preceding claims, wherein the formulation is administered prophylactically.

26. The formulation for use or method according to any of the preceding claims, wherein the formulation comprises niclosamide in the free-acid form.

27. The formulation for use or method according to any one of claims, 1 to 25, wherein the formulation comprises a pharmaceutically acceptable salt of niclosamide.

28. The formulation according to claim 27, wherein the pharmaceutically acceptable salt is niclosamide ethanolamine.

29. The formulation for use or method according to any one of the preceding claims, wherein the formulation is in the form of a solution, suspension (including a nanosuspension) or dispersion of the niclosamide, or a pharmaceutically acceptable salt thereof, and the cyclodextrin in a pharmaceutically acceptable solvent.

30. The formulation for use or method according to claim 29, wherein the solvent comprises water.

31. The formulation for use or method according to claim 29 or claim 30, wherein the solvent further comprises a co-solvent, optionally wherein the co-solvent comprises DMSO, ethanol, propylene glycol, glycerol, a polyethylene glycol with an average molecular weight of 600 or less, or any combination thereof.

32. The formulation for use or method according to claim 31, wherein the co-solvent is present in an amount of from 0 to 20 % by weight, for example from 0 to 10% by weight (e.g. 1 wt.%), based on the weight of the formulation.

33. The formulation for use or method according to any preceding claim, wherein the cyclodextrin comprises b-cyclodextrin or a derivative thereof, optionally wherein the cyclodextrin is hydroxypropyl-p-cyclodextrin (HR-b-CD).

34. The formulation for use or method according to any preceding claim, wherein the niclosamide, or the pharmaceutically acceptable salt thereof, is present in the formulation in an amount of from 0.05 to 10 % by weight, based on the weight of the formulation.

35. The formulation for use or method according to claim 34, wherein the formulation is a liquid formulation and the niclosamide, or the pharmaceutically acceptable salt thereof, is present in the formulation in an amount of from 0.1 to 5 % by weight, e.g. from 0.5 to 2 %, based on the weight of the liquid formulation, optionally wherein the niclosamide, or the pharmaceutically acceptable salt thereof, is present in the formulation in an amount of about 1 % by weight.

36. The formulation for use or method according to any preceding claim, wherein the niclosamide, or the pharmaceutically acceptable salt thereof, is present in the formulation at a concentration of from 1 to 50 mg/ml.

37. The formulation for use or method according to any preceding claim, wherein the cyclodextrin is present in the formulation in an amount of from 1 to 90 % by weight, based on the weight of the formulation.

38. The formulation for use or method according to claim 37, wherein the formulation is a liquid formulation and the cyclodextrin is present in the formulation in an amount of from 1 to 25 % by weight, e.g. from 10 to 20 % by weight, preferably 10 to 15 % by weight, more preferably about 15 % by weight, based on the weight of the formulation.

39. The formulation for use or method according to any preceding claim, wherein at least a portion of the niclosamide, or the pharmaceutically acceptable salt thereof, forms a complex with the cyclodextrin, optionally wherein from about 20 % to about 100 % of the niclosamide, or the pharmaceutically acceptable salt thereof, forms a complex with the cyclodextrin.

40. The formulation for use or method according to any preceding claim, wherein the ratio of the niclosamide, or the pharmaceutically acceptable salt thereof, to cyclodextrin is from 1:250 to 5:1, such as from 1:50 to 1:5, preferably 1:20 to 1:10 e.g. about 1 :10, or e.g. about 1:15.

41. The formulation for use or method according to any preceding claim, wherein the formulation further comprising at least one polymer, optionally wherein the polymer is selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinylalcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA), hydroxypropylcellulose (HPC), poloxamers, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC-AS), and any combination thereof, optionally wherein the polymer comprises PVP.

42. The formulation for use or method according to claim 41, wherein the polymer is present in the formulation in an amount of from 0.05 to 20 % by weight, for example from 0.1 to 15 % by weight (e.g. about 2 wt.%), based on the weight of the formulation.

43. The formulation for use or method according to any preceding claim, wherein the formulation further comprises a preservative, optionally wherein the preservative comprises benzalkonium chloride.

44. The formulation for use or method according to claim 43, wherein the preservative is present in an amount of from 0 to 0.2 % by weight, for example from 0 to 0.1 % by weight (e.g. 0.01 wt.%), based on the weight of the formulation.

45. The formulation for use or method according to any preceding claim, wherein the formulation further comprises a stabilising agent, optionally wherein the stabilising agent comprises disodium edetate, disodium phosphate, polysorbate 80, sodium dihydrogen phosphate, sodium citrate, sodium phosphate, sodium acetate, acetic acid, histidine lactic acid, aspartic acid, tartaric acid, glutamic acid, succinic acid, malic acid, tromethamine, lactic acid, histidine, fumaric acid, citric acid, or any combination thereof.

46. The formulation for use or method according to claim 45, wherein the stabilising agent is present in an amount of from 0 to 2 % by weight, for example from 0.05 to 1 % by weight (e.g. 0.1 wt.%), based on the weight of the formulation.

47. The formulation for use or method according to any preceding claim, wherein the formulation further comprising an electrolyte, optionally wherein the electrolyte comprises sodium chloride, potassium chloride, sodium dihydrogen phosphate, potassium dihydrogen phosphate, or any combination thereof.

48. The formulation for use or method according to claim 48, wherein the electrolyte is present in an amount of from 0 to 10 % by weight, for example from 0.1 to 0.9 % by weight (e.g. 0.5 wt.%), based on the weight of the formulation.

49. The formulation for use or method according to any preceding claim, wherein the formulation has a viscosity of from 1 to 150 cP, optionally from 1.5 to 100, from 2 to 50 or from 5 to 25 cP.

50. The formulation for use or method according to any preceding claim, wherein the formulation has a pH of from 4 to 9, from 6 to 8, or from 7.6-8.0 (e.g. about 7.8).

51. The formulation for use or method according to any one of claims 1 to 25, wherein the formulation is a liquid formulation comprising:

0.5-1.5 % niclosamide ethanolamine;

5-20% cyclodextrin, preferably a b-cyclodextrin, more preferably HR-b-CD;

52. The formulation for use or method according to any one of claims 1 to 25, wherein the formulation is a liquid formulation comprising: about 1 % niclosamide ethanolamine; about 15% cyclodextrin, preferably a b-cyclodextrin, more preferably HR-b-CD; about 2% PVP (e.g. PVP 30); the balance being water, wherein the percentages are by weight based on the weight of the liquid formulation; and wherein the formulation has a pH of from 7.0 to 8.5, for example from 7.5 to 7.8, or from 7.6 to 8.0, preferably about 7.8.

53. The formulation for use or method according to any one of claims 1 to 25, wherein the formulation is a liquid formulation comprising any preceding claim, wherein the formulation has an osmolarity of from 100 to 500 mOsmol/L, for example from 150 to 350 mOsmol/L, preferably from 290 to 320 mOsmol/L.

54. The formulation for use or method according to any of the preceding claims, wherein the formulation is a liquid formulation and said formulation is administered in an amount of from 50 to 500 mI, from 100 to 200 pi or from 130 to 150 mI of a liquid formulation per nostril, for example 140 mI per nostril.

55. The formulation for use or method according to any of the preceding claims, wherein the niclosamide or a pharmaceutically acceptable salt thereof is administered in an amount of from 0.5 to 5 mg per nostril, for example from 1 to 2 mg per nostril or about 1.4 mg per nostril.

56. The formulation for use or method according to any of the preceding claims, wherein the formulation is administered one or twice per day.

57. The formulation for use or method according to any of the preceding claims, wherein the formulation is administered using an intranasal delivery device, for example wherein the formulation is administered as a spray from a metered dose nasal pump device.